Haloguanidine intermediates

ABSTRACT

Compounds useful for inhibiting gastric acid secretion and for the treatment of peptic ulcers caused or exacerbated by gastric acidity having the following formula (I): ##STR1## in which R 1  and R 2 , are H, C 1-10  alkyl, C 3-8  cycloalkyl or cycloalkylalkyl in which the alkyl part is C 1-6  and the cycloalkyl part is C 3-8 , each of the alkyl, cycloalkyl and cycloalkylalkyls being optionally substituted by one or more halogens selected from F, Cl and Br, provided that at least one of R 1  and R 2  is a halogen substituted alkyl, cycloalkyl or cycloalkylalkyl and provided that there is no halogen substituent on the carbon directly attached to the nitrogen; and X, m, Y, n and R 3  are as described in the specification; and the pharmaceutically-acceptable acid-addition salts thereof. Processes for producing compounds of formula (I), pharmaceutical compositions containing them, methods of utilizing such compositions and intermediates useful for synthesizing compounds of formula (I) are also described.

This is a division of application Ser. No. 420,863, filed Sept. 21, 1982and now U.S. Pat. No. 4,604,465 which is a division of Ser. No. 206,005,filed Nov. 12, 1980 and now U.S. Pat. No. 4,362,728.

This invention relates to guanidine derivatives which are histamine H-2antagonists and which inhibit gastric acid secretion.

It is postulated that the physiologically-active compound histamine,which occurs naturally within the animal body, is able to combine, inthe course of exerting its activity, with certain specific receptors ofwhich there are at least two distinct and separate types. The first hasbeen named the H-1 receptor (Ash and Schild, Brit. J. Pharmac. 1966, 27,427) and the action of histamine at this receptor is blocked(antagonised) by classical "antihistamine" drugs such as mepyramine. Thesecond histamine receptor has been named the H-2 receptor (Black et al.,Nature, 1972, 236, 385) and the action of histamine at this receptor isblocked by drugs such as cimetidine. It is known that one of the resultsof the blockade of the action of histamine at the H-2 receptor is theinhibition of the secretion of gastric acid and a compound whichpossesses this ability is therefore useful in the treatment of pepticulcers and other conditions caused or exacerbated by gastric acidity.

In Belgian Pat. No. 866,155, U.S. Pat. Nos. 4,165,377 and 4,165,378 andEuropean Patent Specifications Publication Nos. 0006286, 0006679,0010418 and 0010894 there are described histamine H-2 receptorantagonists which are guanidino heterocycles carrying a side chain tothe end of which is attached a variously-modified guanidine residue. Ithas now been discovered that if the guanidine radical attached to theheterocyclic ring is substituted by a haloalkyl radical there areproduced compounds which are potent histamine H-2 receptor antagonists.

According to the invention there is provided a guanidine derivative ofthe formula: ##STR2## in which

R¹ and R², which may be the same or different, are hydrogen atoms orbranched or unbranched alkyl radicals of 1 to 10 carbon atoms,cycloalkyl radicals of 3 to 8 carbon atoms or cycloalkylalkyl radicalsin which the alkyl part is of 1 to 6 carbon atoms and the cycloalkylpart is of 3 to 8 carbon atoms, each of the alkyl, cycloalkyl andcycloalkylalkyl radicals being optionally substituted by one or morehalogen atoms selected from fluorine, chlorine and bromine atoms,provided that at least one of R¹ and R² is a halogen substituted alkyl,cycloalkyl or cycloalkylalkyl radical and provided that there is nohalogen substituent on the carbon atom of the alkyl, cycloalkyl orcycloalkylalkyl radical which is directly attached to the nitrogen atom;

ring X is a phenyl ring carrying 1 or 2 optional substituents or a 5- or6-membered heterocyclic aromatic ring containing 1, 2 or 3 hetero atomsselected from oxygen, nitrogen and sulphur atoms, which heterocyclicring may, where possible, carry a single optional substitutent, theoptional substituents on ring X being selected from fluorine, chlorine,bromine and iodine atoms and alkyl, alkoxy and alkylthio radicals of 1to 6 carbon atoms, trifluoromethyl, hydroxy and amino radicals;

Y is an oxygen or sulphur atom, a direct bond, a methylene, cis or transvinylene or sulphinyl radical or a radical of the formula NR⁴ in whichR⁴ is a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms;

m is 0 to 4 and n is 1 to 5, provided that when Y is an oxygen atom, asulphinyl radical or a radical of the formula NR⁴, n is 2 to 5;

--R³ is a radical of the formula --A--B in which A is a3,4-dioxocyclobuten-1,2-diyl radical or a radical of the formula C═Z inwhich Z is an oxygen or sulphur atom or a radical of the formula NCN,NNO₂, CHNO₂, NCONH₂, C(CN)₂, NCOR⁵, NCOR₂ ⁵ NSO₂ R⁵ or NR⁶ in which R⁵is an alkyl or haloalkyl radical of 1 to 6 carbon atoms, an aryl oralkylaryl radical of 6 to 10 carbon atoms or a 5- or 6-memberedheterocyclic aromatic radical containing 1, 2 or 3 hereto atoms selectedfrom oxygen, nitrogen and sulphur atoms and R⁶ is a hydrogen atom, analkyl or haloalkyl radical of 1 to 6 carbon atoms or an aryl oralkylaryl radical of 6 to 10 carbon atoms;

B is an alkyl, alkoxy or alkylthio radical of 1 to 6 carbon atoms or aradical of the formula NR⁷ R⁸ in which R⁷ and R⁸, which may be the sameor different, are hydrogen atoms, alkyl, haloalkyl or alkoxycarbonylradicals of 1 to 6 carbon atoms, alkenyl or alkynyl radicals of 3 to 6carbon atoms in which the double or triple bond respectively isseparated from the nitrogen atom of NR⁷ R⁸ by at least one carbon atom,(primary hydroxy)alkyl or (primary amino)alkyl radicals of 2 to 6 carbonatoms, alkylaminoalkyl of dialkylaminoalkyl radicals of up to 8 carbonatoms in which the nitrogen atom is separated from the nitrogen atom ofNR⁷ R⁸ by at least two carbon atoms or cycloalkyl radicals of 3 to 8carbon atoms, or R⁷ and R⁸ are alkyl and are joined to form, togetherwith the nitrogen atom to which they are attached, a 5- or 6 -memberedsaturated ring which optionally contains an oxygen atom or an NR⁹radical in which R⁹ is a hydrogen atom or an alkyl radical of 1 to 6carbon atoms;

or --R³ is a radical of the formula:

    --A.sup.1 --NH--(CH.sub.2).sub.q --Y.sup.1 --(CH.sub.2).sub.p --Het II

in which Y¹ has any one of the values given above for Y, p is 0 to 4 andq is 1 to 5, provided that when Y¹ is an oxygen atom, a sulphinylradical or a radical of the formula NR⁴ q is 2 to 5, and A¹ has one ofthe values given above for A, or --A¹ -- is a radical of the formula:

    --A.sup.2 --E.sup.1 --G--E.sup.2 --A.sup.3 --              III

in which A² and A³, which may be the same or different, have one of thevalues given above for A, E¹ and E², which may be the same or different,are oxygen or sulphur atoms or NH radicals, G is an alkylene,alkenylene, alkynylene or hydroxyalkylene radical of 2 to 12 carbonatoms

and Het-- is a radical of the formula: ##STR3## in which R¹, R² and Xindependently have the meanings stated above;

or Het-- is an oxazol-4-yl, thiazol-4-yl or imidazol-4-yl radicalsubstituted in the 2-position by a radical of the formula: ##STR4## inwhich R¹⁰ is a hydrogen atom, an alkyl or alkanoyl radical of 1 to 6carbon atoms or an aroyl radical of up to 11 carbon atoms;

or Het-- is a 1,2,4-thiadiazol-3-yl or 1,2,4-oxadiazol-3-yl radicalsubstituted in the 5-position by a radical of the formula V in which R¹⁰has the meaning given above;

or Het is an unfused nitrogen-containing 5- or 6-membered monocyclicheterocyclic ring which is optionally substitued by an alkyl or alkoxyradical of 1 to 6 carbon atoms, a hydroxy, trifluoromethyl,hydroxymethyl or amino radical or by a halogen atom;

or Het-- is a radical of the formula: ##STR5## in which R¹¹ and R¹²,which may be the same or different are hydrogen atoms or alkyl, alkenyl,alkynyl, cycloalkyl, trifluoroalkyl or alkyl substituted by a hydroxy,alkoxy, amino, alkylamino or dialkylamino radical each being a total ofup to 8 carbon atoms, or aralkyl radicals of up to 12 carbon atoms orwhen R¹¹ and R¹² are alkyl, they are joined to form, together with thenitrogen atom to which they are attached, a 5- to 10-membered alicyclicheterocyclic ring; M is a straight or branched chain alkylene radical of1 to 6 carbon atoms; and --Het¹ -- is a furan or thiophene ring linkedthrough the 2 and 5 positions, a pyridine ring linked through the 2 and6 positions or a phenyl ring linked through the 1 and 3 or 1 and 4positions;

or --R³ is a radical of the formula: ##STR6## in which R¹³ is a hydrogenatom, an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl radical of up to 6carbon atoms, an aryl radical of 6 to 10 carbon atoms or an arylalkylradical in which the aryl part is of 6 to 10 carbon atoms and the alkylpart is 1 to 6 carbon atoms and R¹⁴ and R¹⁵, which may be the same ordifferent, are hydrogen atoms, alkyl, alkenyl, hydroxyalkyl oralkoxyalkyl radicals of up to 6 carbon atoms or phenylalkyl orpyridylalkyl radicals in which the alkyl part is of 1 to 6 carbon atoms,or R¹⁴ and R¹⁵ are alkyl and joined to form, together with the nitrogenatom to which they are attached, a 5- to 7-membered saturatedheterocyclic ring which may optionally contain an oxygen atom or an NHradical, or R¹⁴ and R¹⁵ taken together represent the group ═CR¹⁶ R¹⁷ inwhich R¹⁶ is a phenyl or pyridyl radical and R¹⁷ is a hydrogen atom oran alkyl radical of 1 to 6 carbon atoms;

or --R³ is a radical of the formula: ##STR7## in which U is an alkyleneradical of 2 to 4 carbon atoms which is optionally substituted by one ortwo radicals selected from alkyl radicals of 1 to 6 carbon atoms andphenylalkyl, furylalkyl, thienylalkyl and pyridylalkyl radicals in whichthe alkyl part is of 1 to 6 carbon atoms and the phenyl or heterocyclicring is optionally substituted by 1 or 2 halogen atoms or methyl ormethoxy radicals;

or --U-- is a radical of the formula:

    --CH.sub.2 --NR.sup.18 --CH.sub.2 --                       IX

in which R¹⁸ is one of the optional substituents, given above, on U whenit is an alkylene radical;

or --R³ is a radical of the formula: ##STR8## in which R¹⁹ is a hydrogenatom or one of the optional substituents on U, given above, when it isan alkylene radical and R²⁰ is a hydrogen atom or an alkyl radical of 1to 6 carbon atoms;

or --R³ is a radical of the formula XI, XII, XIII or XIV: ##STR9## inwhich D is an oxygen or sulphur atom, R²² is a hydrogen atom or an alkylradical of 1 to 6 carbon atoms and R²¹ is a hydrogen atom, an alkylradical of 1 to 6 carbon atoms or a radical of the formula:

    (CH.sub.2).sub.r --W--(CH.sub.2).sub.s --R.sup.23          XV

in which

W is an oxygen or sulphur atom or a methylene radical;

r and s together are 1 to 4 when W is an oxygen or sulphur atom and rand s together are 0 to 4 when W is a methylene radical;

R²³ is a cycloalkyl radical of 3 to 6 carbon atoms or a naphthyl radicalor a phenyl radical optionally substituted by a methylenedioxy orethylenedioxy radical or, in the 2, 3, 4 or 5 positions, by one or more(same or different) halogen atoms or alkyl, alkoxy or haloalkyl radicalsof 1 to 6 carbon atoms, arylalkoxy radicals in which the aryl part is of6 to 10 carbon atoms and the alkoxy part is of 1 to 6 carbon atoms,alkoxyalkoxy radicals of 3 to 8 carbon atoms, dialkylamino radicals of 2to 8 carbon atoms, alkoxyphenyl or alkoxyphenoxy radicals in which thealkoxy part is of 1 to 6 carbon atoms, hydroxy, phenyl, halophenyl orphenoxy radicals or R²³ is a pyridine, pyridine-N-oxide, furan,thiophene, thiazole, oxazole, isothiazole, imidazole, pyrimidine,pyrazine, pyridazine, thiadiazole, quinoline, isoquinoline,benzimidazole, benzthiazole or indole ring each optionally substitutedby a halogen atom, an alkyl or alkoxy radical of 1 to 6 carbon atoms ora hydroxy or amino radical;

or --R³ is a pyrimid-2-yl or imidazol-2-yl radical to which isoptionally fused a benzene ring, the pyrimidine and imidazole rings, oralternatively the optionally fused benzene ring, carrying 1 or 2optional substituents selected from the group which is optionallysubstituted on ring X; and the pharmaceutically-acceptable acid-additionsalts thereof.

It is to be understood that, in the above formulae I, IV, V, VII, VIII,X, XI, XII, XIII and XIV and throughout this specification, although thedouble bonds in both side chains attached to ring X have been insertedin particular positions, various other tautomeric forms are possible,and this invention includes such tautomeric forms within its scope, bothin terms of the compound of the invention and in terms of themanufacturing processes. It is further to be understood that the lettersC, H, N, O and S are the universally accepted contractions for theelements carbon, hydrogen, nitrogen, oxygen and sulphur respectively.

A particular value for R¹ or R² when it is a substituted alkyl radicalis a 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,2-bromo-2,2-difluoroethyl, 2,2-dibromo-2-fluoroethyl, 2-fluoroethyl,2-chloroethyl, 2,2-difluoroethyl, 2,2-dichloroethyl,2-chloro-2-fluoroethyl, 2-bromo-2-fluoroethyl,2,2,3,3,3-pentafluoropropyl, 1,1,1,3,3,3-hexafluoroisopropyl,1,3-dichloro-1,1,3,3-tetrafluoroisopropyl,1-chloro-1,1,3,3,3-pentafluoroisopropyl, 1,3-difluoroisopropyl or2,2,3,3,4,4,4-heptafluorobutyl radical.

A particular value for R¹ or R² when it is a substituted cycloalkylradicl is a 2,2,3,3-tetrafluorocyclopropyl,2-chloro-2,3,3-trifluorocyclopropyl, 2,2-difluorocyclopropyl,2-chloro-3,3-difluorocyclopropyl, 2,2,3,3,4,4-hexafluorocyclobutyl or2-chloro-2,3,3,4,4-pentafluorocyclobutyl radical.

A particular value for R¹ or R² when it is a substituted cycloalkylalkylradical is a (1,2,2,3,3-pentafluorocyclopropyl)methyl,(2-chloro-1,2,3,3-tetrafluorocyclopropyl)methyl,(1,2,2,3,3,4,4-heptafluorocyclobutyl)methyl or(2-chloro-1,2,3,3,4,4-hexafluorocyclobutyl)methyl radical.

A particular value for R¹ and R² when it is an alkyl radical is amethyl, ethyl, propyl, isopropyl or butyl radical.

A particular value for R¹ or R² when it is a cycloalkyl radical is acyclopropyl or cyclobutyl radical.

A particular value for R¹ or R² when it is a cycloalkylalkyl radical isa cyclopropylmethyl or cyclobutylmethyl radical.

A particular value for ring X is a phenyl, thiophene, pyridine,pyrimidine, imidazole, thiazole, oxazole, pyrazole, triazole, e.g.1,2,4-triazole, thiadiazole, e.g. 1,2,4-thiadiazole, oxadiazole, e.g.1,2,4-oxadiazole, pyrazine, pyridazine, isothiazole, isoxazole ortriazine, e.g. 1,3,5-triazine ring.

A particular value for the optional substituent on ring X when it is analkyl, alkoxy or alkylthio radical is a methyl, methoxy or methylthioradical.

A particular value for R⁴ when it is an alkyl radical is a methylradical.

A particular value for R⁵ is a methyl, ethyl, n-propyl, i-propyl,n-butyl, trifluoromethyl, 2,2,2-trifluoroethyl, phenyl, p-tolyl orpyridyl radical, the halogen of the haloalkyl being fluoro, chloro orbromo.

A particular value for R⁶ is a hydrogen atom or a methyl,2,2,2-trifluoroethyl, phenyl or p-tolyl radical, the halogen of thehaloalkyl being fluoro, chloro or bromo.

A particular value for B when it is an alkyl, alkoxy or alkylthioradical is a methyl, ethyl, methoxy, ethoxy or methylthio radical.

A particular value for R⁷ or R⁸ is a hydrogen atom or a methyl, ethyl,i-propyl, 2,2,2-trifluoroethyl, methoxycarbonyl, ethoxycarbonyl, allyl,propargyl, 2-hydroxyethyl, 2-aminoethyl, 2-methylaminoethyl,2-dimethylaminoethyl, 2-diethylaminoethyl, cyclohexyl or phenyl radical,the halogen of the haloalkyl being fluoro, chloro or bromo.

A particular value for R⁷ and R⁸ when they are joined to form a ring isa pyrrolidine, piperidine, morpholine or piperazine ring.

A particular value for R⁹ is a hydrogen atom or a methyl radical.

A particular value for G is an ethylene, trimethylene, tetramethylene,but-2-enylene, but-2-ynylene or 2-hydroxytrimethylene radical.

A particular value for R¹⁰ is a hydrogen atom or a methyl, n-butyl,acetyl, propionyl or benzoyl radical.

A particular value for Het when it is an unfused nitrogen-containing 5-or 6-membered monocyclic heterocyclic ring is one of the particularvalues given above for ring X. A particular value for the optionalsubstituent on such a ring when it is an alkyl or alkoxy radical is amethyl or methoxy radical, the optional halogen being fluoro, chloro orbromo.

A particular value for R¹¹ or R¹² is a hydrogen atom or a methyl, allyl,propargyl, cyclohexyl, trifluoromethyl, 2-hydroxyethyl, 2-methoxyethyl,2-aminoethyl, 2-methylaminoethyl, 2-dimethylaminoethyl,cyclopropylmethyl or benzyl radical.

A particular value for R¹¹ and R¹² when they are joined to form a ringis a pyrrolidine, piperidine, piperazine or morpholine ring.

A particular value for M is a methylene, ethylene or trimethyleneradical.

A particular value for R¹³ is a hydrogen atom or a methyl, allyl,2-hydroxyethyl, 2-methoxyethyl, phenyl or benzyl radical.

A particular value for R¹⁴ or R¹⁵ is a hydrogen atom or a methyl, allyl,2-hydroxyethyl, 2-methoxyethyl, benzyl or pyridylmethyl radical.

A particular value for R¹⁴ and R¹⁵ when they are joined to form a ringis a pyrrolidine, piperidine, piperazine or morpholine ring.

A particular value for R¹⁷ when it is an alkyl radical is a methylradical.

A particular value for the optional substituent on U when U is analkylene radical is a methyl, benzyl, 2-furylmethyl, 2-thienylmethyl or2-pyridylmethyl radical.

A particular value for R¹⁸ is one of the particular values given abovefor the optional substituent on U when it is an alkylene radical.

A particular value for R¹⁹ is a hydrogen atom or one of the particularvalues given above for the optional substituent on U when U is analkylene radical.

A particular value for R²⁰ is a hydrogen atom or a methyl radical.

A particular value for R²¹ or R²² when it is an alkyl radical is amethyl radical.

A particular value for R²³ when it is a cycloalkyl radical is acyclohexyl radical.

A particular value for the optional substituent on R²³ when R²³ is aphenyl radical is a fluorine, chlorine or bromine atom or amethylenedioxy, ethylenedioxy, methyl, methoxy, trifluoromethyl,benzyloxy, 2-methoxyethoxy, dimethylamino, 4-methoxyphenyl,4-methoxyphenoxy, hydroxy, phenyl, 4-chlorophenyl, 4-bromophenyl orphenoxy radical, the halogen of the haloalkyl or halophenyl beingfluoro, chloro or bromo.

A particular value for the optional substituent on R²³ when R²³ is aheterocyclic ring is a fluorine, chlorine or bromine atom or a methyl,methoxy, hydroxy or amino radical.

A particular value for the optional substituent on R³ when R³ is apyrimid-2-yl or imidazolyl-2-yl radical to which is optionally fused abenzene ring is one of the particular values for the optionalsubstituent on ring X given above.

The following are twelve preferred features of the guanidine derivativeof the formula I. When any one of these features is taken, either singlyor in combination, with the other general or particular features of theguanidine derivative of the formula I listed above, there are obtainedpreferred sub-groups of compounds within the above general definition.

1. R¹ and/or R² carries at least one fluorine atom on the carbon atomwhich is one carbon atom removed from the nitrogen atom to which theradical is attached.

2. R² is a hydrogen atom.

3. Ring X is a phenyl, pyridine, pyrimidine, thiazole, pyrazole,thiadiazole, pyrazine or triazine ring.

4. R³ is a radical of the formula --A--B in which A is a radical of theformula C═Z in which Z is an oxygen atom and B is an alkyl radical.

5. R³ is a radical of the formula --A--B in which A is a radical of theformula C═Z in which Z is a radical of the formula NCN, CHNO₂ or NSO₂ R⁵and B is a radical of the formula NHR⁷.

6. R³ is a radical of the formula XI or XII.

7. m is 0.

8. R¹ is a 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,2-chloro-2,2-difluoroethyl, 2,2-difluoroethyl,2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl,1,1,1,3,3,3-hexafluoroisopropyl or 1,1,1-trifluoroisopropyl radical, andR² is a hydrogen atom.

9. Ring X is a 1,3-disubstituted phenyl ring, a pyrimidine ring in whichthe guanidine radical is substituted at the 4-position and (CH₂)_(m) atthe 2-position, a 2,6-disubstituted pyrazine ring or a 2,6-disubstitutedpyridine ring.

10. Y is a direct bond and m+n is 4 or 5.

11. Y is a sulphur or oxygen atom or an NH radical, m is 0 and n is 2, 3or 4.

12. R¹ is a 2,2,2-trifluoroethyl or 2,2,3,3,3-pentafluoropropyl radical.

Specific compounds of the invention are set out in the Examples. Thefollowing is a preferred group of compounds:

5-(4-chlorobenzyl)-2-(4-[2-(2,2,2-trifluoroethyl)guanidinothiazol-4-yl]butylamino)pyrimid-4-one;

6-(3-methoxybenzyl)-3-(2-[2-(2,2,2-trifluoroethyl)guanidinothiazol-4-yl]butylamino)-1,2,4-triazin-5-one;

3-amino-5-(2-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]ethylamino-1H-1,2,4-triazole;

4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-methanesulphonyl-3-[2,2,2-trifluoroethyl]guanidino)propylthio]pyrimidine;

4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2,3-bis[2,2,2-trifluoroethyl]guanidino)propylthio]pyrimidine;

2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-[2-(2,2,2-trifluoroethyl)guanidino]butyl)thiazole;

6-methyl-2-(5-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]pentylamino)pyrimid-4-one;

2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-acetamidobutyl)thiazole;

2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-cyano-2-methylamidino)butyl]thiazole;

5-methyl-2-(4-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]butylamino)pyrimid-4-one;

2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-ethylamidino)pentyl]thiazole;

2-[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]benzimidazole;

3-amino-1-methyl-5-[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]-1H-1,2,4-triazole;

4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(2-cyano-3-methylguanidino)butyl]pyrimidine;

1-[4-(2-[(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]-1-methylamino-2-nitroethylene;

2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(2-methylsulphonyl-3-methylguanidino)butyl]thiazole;

2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(2-cyanoguanidino)butyl]thiazole;

4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-cyano-3-methylguanidino)propylthio]pyrimidine;

1-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-ylthio)propylamino]-1-methylamino-2-nitroethylene;

4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-cyano-3-methylguanidino)propyloxy]pyrimidine;

4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-methanesulphonyl-3-[2,2,2-trifluoroethyl]guanidino)propylthio]pyrimidine;

and the pharmaceutically acceptable acid-addition salts thereof.

A suitable pharmaceutically-acceptable acid-addition salt of theguanidine derivative of the invention is, for example, a salt formedwith hydrochloric, hydrobromic, phosphoric, sulphuric, acetic, citric ormaleic acid.

The guanidine derivative of the invention may be manufactured by methodsknown in themselves for the manufacture of chemically-analogouscompounds. The following processes, (X, Y, m, n, A, B, A¹, A², A³, E¹,E², G, W, q, p, r, s, Het, Het¹, U, D and R¹ to R²³ inclusive having themeanings stated above), are therefore provided as further features ofthe invention.

The process of the invention is characterised by:

(a) reaction of a compound of the formula: ##STR10## with a compound ofthe formula R²⁴ --R³ in which R²⁴ is a displaceable radical. When R³ isa radical of the formula A--B or of the formula II R²⁴ is preferably amethoxy, ethoxy or methylthio radical. When R³ is a radical of theformula VII, VIII, X, XI, XII, XIII or XIV or a pyrimid-2-yl orimidazolyl-2-yl radical, R²⁴ is preferably a halogen atom, a methylthioor benzylthio radical. The reaction may be carried out in the absence ofa diluent or solvent, or in the presence of a diluent or solvent such asmethanol, ethanol, acetonitrile or pyridine. The reaction may beaccelerated or completed by the application of heat, for example byheating to the boiling point of the diluent or solvent.

(b) for those compounds in which R³ is a radical of the formula A--B inwhich B is an alkoxy or alkylthio radical or a radical of the formulaNR⁷ R⁸ or R³ is a radical of the formula II, reaction of a compound ofthe formula: ##STR11## in which R²⁴ is a displaceable radical and A⁴ hasone of the values given for A or A¹ with a compound of the formula R²⁵--H in which R²⁵ is an alkoxy or alkylthio radical of 1 to 6 carbonatoms, a radical of the formula NR⁷ R⁸ or a radical of the formula:

    HN--(CH.sub.2).sub.q --Y.sup.1 --(CH.sub.2).sub.p --Het    XVIII

The process may be carried out using an excess of R²⁵ --H. R²⁴ ispreferably a methoxy, ethoxy or methylthio radical. The process may becarried out in a diluent or solvent such as water, methanol, ethanol orpyridine. The process may be accelerated by the application of heat, forexample by heating to the boiling point of the diluent or solvent.

(c) for those compounds in which R³ is a radical of the formula A--B inwhich A is a radical of the formula C═Z in which Z is a sulphur oroxygen atom and B is a radical of the formula NR⁷ R⁸ in which R⁸ is ahydrogen atom and R⁷ has the value stated above other than ahydroxyalkyl, aminoalkyl, or alkylaminoalkyl radical, or R³ is a radicalof the formula II in which A¹ is a radical of the formula C═Z in which Zis a sulphur or oxygen atom, reaction of a compound of the formula XVIwith a compound of the formula R²⁶ --N═C═D or alternatively reaction ofa compound of the formula: ##STR12## with a compound of the formula R²⁶--NH₂ in which D is a sulphur or oxygen atom and R²⁶ is a hydrogen atomor an alkyl, haloalkyl, alkenyl, alkynyl, dialkylaminoalkyl, cycloalkylor phenyl radical, or a radical of the formula:

    (CH.sub.2).sub.q --Y.sup.1 --(CH.sub.2).sub.p --Het        XX

When D is a sulphur atom the reaction is preferably carried out in adiluent or solvent such as methanol or ethanol. When D is an oxygen atoma non-alcoholic diluent or solvent must be used.

(d) for those compounds in which R² is a hydrogen atom, reaction of acompound of the formula: ##STR13## with ammonia. The process may becarried out in ethanol or methanol which is saturated with ammonia.

(e) for those compounds in which R³ is a radical of the formula A--B inwhich A is a radical of the formula C═Z in which Z is a radical of theformula NCN and B is a radical of the formula NR⁷ R⁸ in which R⁷ and R⁸are hydrogen atoms, reaction of a compound of the formula XVI withdicyanimide or a salt thereof. The process is preferably carried outusing the sodium salt of dicyanimide, in a diluent or solvent such asn-butanol. The reaction may be accelerated or completed by theapplication of heat, for example by heating to the boiling point of thediluent or solvent.

(f) for those compounds in which R³ is a radical of the formula VII inwhich R¹³ is other than a hydroxyalkyl radical and R¹⁴ and R¹⁵ arehydrogen atoms, reaction of a compound of the formula I in which R³ is aradical of the formula A--B in which A is a radical of the formula C═Zin which Z is a radical of the formula NCN and B is an alkoxy oralkylthio radical, with a compound of the formula:

    H.sub.2 NNHR.sup.27                                        XXII

in which R²⁷ is a hydrogen atom or an alkyl, alkenyl, alkoxyalkyl, arylor arylalkyl radical. The process may be carried out in a diluent orsolvent such as ethanol or dimethylformamide, and may be accelerated orcompleted by heating, for example by heating to the boiling point of thediluent or solvent.

(g) for those compounds in which R³ is a radical of the formula A--B inwhich B is a radical of the formula C═Z, reaction of a compound of theformula XVI with a compound of the formula:

    Z═C═NR.sup.7                                       XXIII

The process may be carried out in a diluent or solvent such as ethanolor dimethylformamide.

(h) for those compounds in which the optional halogen substituent onring X is a chlorine or bromine atom, chlorination or bromination of thecorresponding unsubstituted compound. The reaction may be carried out ina diluent or solvent such as chloroform or methylene chloride.

(i) for those compounds in which R³ is a radical of the formula A--B inwhich A is a radical of the formula C═Z in which Z is a radical of theformula NR⁶ and B is a radical of the formula NHR⁷, reaction of acompound of the formula: ##STR14## with a compound of the formula R⁶NH₂. The reaction may be carried out in a diluent or solvent such asdimethylformamide.

(j) for those compounds in which R³ is a radical of the formula A--B inwhich A is a radical of the formula C═Z in which Z is an oxygen orsulphur atom and B is an alkyl radical, reaction of a compound of theformula XVI with an acid, or an acylating agent derived from an acid, ofthe formula R³⁰ CD₂ H in which R³⁰ is a hydrogen atom or an alkylradical of 1 to 6 carbon atoms and D is an oxygen or sulphur atom. Theprocess may be carried out in an inert diluent or solvent, and in thepresence of a base, at or below room temperature. The diluent or solventpreferably is, or contains, pyridine which also acts as the base. When Dis an oxygen atom, the reaction is preferably carried out using the acidchloride or acid anhydride as the acylating agent.

(k) for those compounds in which R³ is an imidazol-2-yl radical to whichis fused an optionally-substituted benzene ring, cyclisation of acompound of the formula: ##STR15## in which R²⁸ and R²⁹ are the optionalsubstituents on the benzene ring. The process may be conducted in adiluent or solvent such as dimethylformamide.

(l) for those compounds in which Y is a sulphinyl radical, oxidation ofthe corresponding compound in which Y is a sulphur atom. The process maybe carried out using a mild oxidizing agent such as sodiummetaperiodate, in a diluent or solvent such as aqueous methanol oraqueous ethanol.

(m) for those compounds in which R³ is a radical of the formula A--B orII in which A, A¹, A² or A³ is a radical of the formula C═Z in which Zis a radical of the formula NCONH₂, hydrolysis of the correspondingcompound in which Z is a radical of the formula NCN. The process may becarried out using a dilute mineral acid, for example dilute hydrochloricacid, in a diluent or solvent such as water. The reaction may beaccelerated or completed by the application of heat, for example byheating to the boiling point of the diluent or solvent.

(n) for those compounds in which Y is an oxygen or sulphur atom or aradical of the formula NR⁴, reaction of a compound of the formula:##STR16## in which Q is an oxygen or sulphur atom or a radical of theformula NR⁴ with a compound of the formula:

    R.sup.24 --(CH.sub.2).sub.n --NH--R.sup.3                  XXVII

in which R²⁴ is a displaceable radical.

When the process of the invention manufactures the compound of theformula I in the form of the free base and an acid-addition salt isrequired, the compound of the formula I in the free base form is reactedwith an acid which affords a pharmaceutically-acceptable anion.

A critical starting material for use in a number of the above processesis the compound of the formula XVI. This compound may also be used as anintermediate in the preparation of starting materials for a number ofother processes. The compound of the formula XVI is therefore consideredto be a further feature of the present invention.

The compound of the formula XVI may be prepared in a number of waysdepending on the nature of the ring X and on the nature of Y. In generalterms the two side chains attached to ring X may be constructed onebefore the other, in either order, starting either from a suitablysubstituted ring X or by constructing ring X itself from subfragments.When Y is a direct bond, a methylene or vinylene radical, it isgenerally convenient to start with a ring X carrying this side chain inwhich the terminal nitrogen atom is suitably protected (for example inthe form of a phthalimido residue) or so to construct ring X that such aside chain inserted at the same time. On the other hand when Y is anoxygen or sulphur atom, a sulphinyl radical or a radical of the formulaNR⁴, it is generally convenient to introduce Y at a later stage of thesynthesis. These general principles can be illustrated with reference tosyntheses of specific ring systems.

When ring X is a pyrimidine in which the guanidine is attached to the4-position and the other side chain to the 2-position and Y is a directbond, a methylene or vinylene radical, the compound of the formula XVImay be obtained as follows. Reaction of a compound of the formula:##STR17## with an optionally substituted 2-chloroacrylonitrile gives the2-substituted-4-aminopyrimidine. When R² is a hydrogen atom, thiscompound is then reacted with a compound of the formula R¹ NCS to formthe corresponding thiourea which is treated with ammonia in the presenceof mercuric oxide to give the guanidine (via the carbodiimide asintermediate). Finally the amine is liberated from its protecting group.This reaction sequence is illustrated in Example 4. When R² is otherthan hydrogen, the aminopyrimidine is reacted with a cyanamide of theformula R¹ R² N--C.tbd.N to give the guanidine directly. Alternativelywhen R² is other than hydrogen, the aminopyrimidine may be treated withbenzoylisothiocyanate to give the corresponding benzoylthiourea. Thebenzoyl group is removed and H₂ S is removed from the monosubstitutedthiourea by reaction with mercury to give the correspondingmonosubstituted cyanamide. This is then reacted with an amine of theformula R¹ R² NH to give the guanidine. Finally the amine is liberatedfrom its protecting group as before. An example of this reactionsequence as applied to a 1,3-disubstituted pyrazole ring is illustratedin Example 43 in which the amine is protected in the form of a cyanoradical.

When ring X is a pyrimidine in which the guanidine is attached to the4-position and the other side chain to the 2-position and Y is a sulphuror oxygen atom or a radical of the formula NR⁴, the compound of theformula XVI may be obtained as follows. A compound of the formula:##STR18## in which R²⁴ is a displaceable radical and R³⁰ is the optionalsubstituent on ring X is reacted with a compound of the formula:##STR19## to give the compound of the formula: ##STR20##

The free amino radical is then elaborated to form the substitutedguanidine, as described above, and the amine is finally liberated fromthe protecting group. This reaction sequence is illustrated in Example21. An alternative sequence in which the positions of R²⁴ and Y--H areinterchanged is illustrated in Examples 16, 27 and 42. A furtheralternative sequence in which the substituted guanidine radical isformed before elaboration of the side chain is illustrated in Example34. Examples of this further alternative sequence as applied to ring Xwhen it is a 1,3-disubstituted benzene ring, a 2,6-disubstitutedpyrazine ring and 2,6-disubstituted pyridine ring are illustrated inExamples 88, 86 and 32 respectively.

When ring X is a thiazole ring in which the guanidine is attached to the2-position and the other side chain to the 4-position and Y is a sulphuror oxygen atom or a radical of the formula NR⁴, the compound of theformula XVI may be obtained as follows. An amine of the formula R¹ R² NHis reacted with sodium dicyanamide to give the compound of the formula:##STR21## which is in turn reacted with thioacetamide and an acid (asource of H₂ S) to give the amidinothiourea of the formula: ##STR22##

This amidinothiourea is then reacted with a compound of the formula:

    ClCHR.sup.31 CO(CH.sub.2).sub.m Cl                         XXXIII

in which R³¹ is a hydrogen atom or the optional substituent on ring X togive the compound of the formula: ##STR23## This compound is thenreacted with a compound of the formula:

    H--Y--(CH.sub.2).sub.n --NH.sub.2                          XXXV

to give the compound of the formula XVI. This reaction sequence isillustrated in Examples 2 and 69 to 74 inclusive.

When ring X is a thiazole ring in which the guanidine is attached to the2-position and the other side chain to the 4-position and Y is a directbond, a methylene or vinylene radical, the compound of the formula XVImay be obtained as follows. The compound of the formula XXXII is reactedwith a compound of the formula: ##STR24## in which R³¹ is a hydrogenatom or the optional ring substituent to give the compound of theformula: ##STR25## The protecting group is then removed to give therequired product. This reaction sequence is illustrated in Examples 6,14, 45 and 51.

When ring X is a 1,2,4-thiadiazole ring in which the guanidine isattached at the 5-position, the other side chain is attached at the3-position, m is 1 to 4 and Y is a sulphur or oxygen atom or a radicalof the formula NR⁴, the compound of the formula XVI may be obtained asfollows. A compound of the formula XXXII is reacted with bromine to givethe compound of the formula: ##STR26## This compound is then reactedwith a compound of the formula: ##STR27## in which THPO stands for atetrahydropyranyl ether protecting group to give the compound of theformula: ##STR28## The protecting group is removed and the side chain iselaborated by standard chemical methods. This reaction sequence isillustrated in Example 89.

The above general methods can be applied to other substitution patternswithin the same ring X systems, and can also be applied to other ring Xsystems not discussed above. Alternatively, Smith, Kline and Frenchpatents such as British Pat. No. 1,338,169 describe a number ofdifferent compounds of the general formula: ##STR29## In this type ofcompound, the amino group attached to (CH₂)_(n) is much more basic thanthat attached to ring X, and the former may thus be selectively reactedwith a protecting group. The guanidine residue may then be formed by oneof the methods described above and finally the protecting group removedto give the compound of the formula XVI.

When Y is a sulphinyl radical, the compound of the formula XVI may beprepared by mild oxidation of the corresponding compound in which Y is asulphur atom.

The compound of the formula XVII for use in process (b) may be preparedby reaction of the compound of the formula XVI with a compound of theformula R²⁴ -A⁴ -R²⁴, for example as described in Examples, 3, 4, 6, 8,10, 16, 19, 20, 23, 24, 25, 27, 30, 32, 35, 36, 41, 42, 43, 45, 51, 54,57, 67, 69, 70, 71, 72, 73, 74, 75, 76, 77, 82, 84, 85, 88 and 89.

The compound of the formula XIX for use in process (c) may be preparedby reaction of the compound of the formula XVI withthiocarbonyldimidazole or carbonyldiimidazole, for example as describedin Example 61.

The compound of the formula XXI for use in process (d) may be preparedby reaction of a compound of the formula: ##STR30## (many of which areknown compounds, others of which may be prepared by modifications of theprocesses described above) with a compound of the formula R¹ NCS to givethe corresponding thiourea. This thiourea is treated with yellowmercuric oxide to give the carbodiimide of the formula XXI which ispreferably then reacted as described in process (d) in situ withoutisolation, for example as described in Examples 1, 25 and 31.

The compound of the formula XXIII for use in process (g) may be preparedby reaction of a compound of the formula: ##STR31## with yellow mercuricoxide or silver nitrite to give the carbodiimide which is preferablyreacted as described in process (g) in situ without isolation, forexample as described in Examples 26, 37, 44 and 48.

The compound of the formula XXIV for use in process (i) may be preparedfrom the compound of the formula I in which R³ is a radical of theformula A--B in which A is a radical of the formula C═Z in which Z is asulphur atom and B is a radical of the formula NR⁷ R⁸ in which R⁸ is ahydrogen atom by reaction with yellow mercuric oxide to give thecarbodiimide which is preferably reacted as described in process (i) insitu without isolation, for example as described in Example 47.

The compound of the formula XXV for use in process (k) may be preparedby reaction of a compound of the formula XIX in which D is a sulphuratom with a compound of the formula:

    H.sub.2 N--CHR.sup.28 ═CR.sup.29 --NH.sub.2            XLIV

The resulting thiourea is treated with silver nitrate and thecarbodiimide of the formula XXV thus formed is preferably reacted asdescribed in process (k) in situ without isolation, for example asdescribed in Example 65.

As noted above, the guanidine derivative of the invention is a histamineH-2 antagonist, inhibits the secretion of gastric acid in warm-bloodedanimals and is therefore useful in the treatment of peptic ulcers andother conditions caused or exacerbated by gastric acidity, includingstress ulcers and gastrointestinal bleeding due to trauma.

The histamine H-2 antagonist activity may be demonstrated on standardtests, for example by the ability of the compound of the formula I toinhibit the histamine-induced positive chronotropic response in thespontaneously beating right atrium of the guinea pig or by its abilityto inhibit the histamine-induced increase in the level of cyclic AMP (inthe presence of a phosphodiesterase inhibitor) in a free cell suspensionobtained from canine gastric mucosa.

The guinea pig atrium test is carried out as follows:

A guinea pig right atrium is suspended at 1 g. tension (isometric) in athermostatically-controlled (30° C. ) tissue bath (25 ml.) containingoxygenated (95% O₂ 5% CO₂) Krebs-Hanseleit buffer (pH 7.4). The tissueis allowed to stabilise over 1 hour during which time it is washed 2-4times. Individual contractions are recorded with a force-displacementtransducer through a strain gauge coupler, and instantaneous rates aremonitored with a cardiotachometer. A control response to 1 μM histamineis obtained after which the tissue is washed 3 times and allowed tore-equilibrate to basal rate. After re-equilibration for 15 minutes, thetest compound is added to the desired final concentration. Ten minutesafter addition of the compound histamine (1 μM) is again added and theresponse to histamine in the presence of antagonist is compared to thehistamine control response. The result is expressed as a percentage ofthe histamine control response. Thereafter the apparent dissociationconstant of the H-2 antagonist is determined by standard procedures.

All the compounds exemplified in this specification are active on theguinea pig atrium test at or below a bath concentration of 10 μM., andthe more active compounds show complete inhibition of response at thisconcentration.

The histamine-stimulated cyclic AMP test is carried out as described byScholes et al, Agents and Actions, 1976, 6, 677-682.

The inhibition of the secretion of gastric acid may be demonstrated instandard tests, for example by the ability of the compound of theformula I, when dosed intravenously, intragastrically or orally, toinhibit the secretion of acidic gastric juice in, for example, rats,cats or dogs provided with gastric fistulae and whose gastric secretionis stimulated by the administration of a secretagogue, for examplepentagastrin or histamine.

The test in dogs is carried out as follows:

A female pure bred beagle (9-12 kg.) having a chronic gastric fistula isfasted overnight with water ad lib. During the experiment the dog islightly restrained in a standing position. When studying the testcompound by the intravenous route, the fistula is opened and, afterascertaining the absence of basal secretion over a period of 30 minutes,a continuous intravenous infusion of secretagogue (0.5 μmole/kg/hour ofhistamine or 2 μg./kg./hour pentagastrin) in saline (15 ml./hour) isbegun. Gastric acid samples are collected every 15 minutes. The volumeof each sample is measured and a 1 ml. aliquot is titrated to neutralitywith 0.1NNaOH to determine acid concentration. When a plateau ofsecretion is reached (1-2 hours), the test compound is administeredintravenously in saline and gastric acid samples are collected for afurther 2-3 hours during which time the infusion of the secretagoguecontinues uninterrupted.

When studying the test compound by the intragastric route, the absenceof basal secretion over a period of 30 minutes is ascertained and thetest compound, contained in 25 ml. of 0.5% w/v hydroxypropylmethylcellulose and 0.1% w/v `Tween` 80 in water (`Tween` is a TradeMark); is instilled into the stomach through a fistula dosing plug. Onehour later, the fistula is reopened and intravenous infusion of asecretagogue, as described above, is immediately begun. Gastric acidsamples are measured as described above and the approach of acidsecretion to a plateau is compared to that of a control animal which isdosed intragastrically only with the dosing vehicle.

When studying the test compound by the oral route, it is administered ina gelatin capsule washed down with 15 ml. of water. One hour later, thefistula is opened and intravenous infusion of the secretagogue isimmediately begun. Gastric acid samples are measured as above and theapproach of acid secretion to a plateau is compared to that of anundosed control animal.

The results obtained in the atrium test are predictive of activity inthe dog test.

No overt toxicity or side effects were noted during the dog tests. Thecompounds1-[4-(2-[(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]-1-methylamino-2-nitroethyleneand2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(2-methylsulphonyl-3-methylguanidino)butyl]thiazolein 10% w/v dimethylsulphoxide in saline (0.3 ml.) were dosed viaintraperitoneal injection to two groups of five male Swiss-Webster mice(25-30 g.) at a dose of 50 mg./kg. and the animals were observed for aperiod of four hours, and again checked 24 hours after dosing. No toxicsymptoms were noted in any of the dosed animals.

According to a further feature of the invention there is provided apharmaceutical composition which comprises a guanidine derivative of theinvention in association with a non-toxic pharmaceutically-acceptablediluent or carrier.

The pharmaceutical composition may, for example, be in a form suitablefor oral, rectal, parenteral or topical administration, for whichpurposes it may be formulated by means known to the art into the formof, for example, tablets, capsules, aqueous or oil solutions orsuspensions, emulsions, dispersible powders, suppositories, sterileinjectable aqueous or oily solutions or suspensions, gels, creams,ointments or lotions.

In addition to the guanidine derivative of the formula I, thepharmaceutical composition of the invention for oral, rectal orparenteral administration may also contain, or be co-administered with,one or more known drugs selected from antacids, for example aluminumhydroxide-magnesium hydroxide mixtures; antipepsin compounds, forexample pepstatin; other histamine H-2 antagonists, for examplecimetidine; ulcer healing agents, for example carbenoxolone or bismuthsalts; anti-inflammatory agents, for example ibuprofen, indomethacin,naproxen or aspirin; prostaglandins, for example16,16-dimethylprostaglandin E₂ ; classical antihistamines (histamine H-1antagonists), for example mepyramine or diphenhydramine; anticholinergicagents, for example atropine or propantheline bromide; anxiolyticagents, for example diazepam, chlordiazepoxide or phenobarbital.

The pharmaceutical composition of the invention for topicaladministration may also contain, in addition to the guanidinederivative, one or more classical anti-histamines (histamineH-1antagonists), for example mepyramine or diphenhydramine and/or one ormore steroidal anti-inflammatory agents, for example fluocinolone ortriamcinolone.

A topical formulation may contain 1-10% w/w of the guanidine derivativeof the invention. A preferred pharmaceutical composition of theinvention is one suitable for oral administration in unit dosage form,for example a tablet or capsule which contains between 10 mg. and 500mg. of the guanidine derivative, or one suitable for intravenous,subcutaneous or intramulscular injection, for example a sterileinjectable containing between 0.1% and 10% w/w of the guanidinederivative.

The pharmaceutical composition of the invention will normally beadministered to man to inhibit gastric acid secretion and for thetreatment of peptic ulcers and other conditions caused or exacerbated bygastric acidity in the same general manner as that employed forcimetidine, due allowance being made in terms of dose levels for thepotency of the guanidine derivative of the present invention relative tocimetidine. Thus each patient will receive an oral dose of between 15 mgand 1500 mg. and preferably between 20 mg. and 200 mg. of guanidinederivative or an intravenous, subcutaneous or intramuscular dose ofbetween 1.5 mg. and 150 mg., and preferably between 5 mg. and 20 mg. ofthe guanidine derivative, the composition being administered 1 to 4times per day. The rectal dose will be approximately the same as theoral dose. The composition may be administered less frequently when itcontains an amount of guanidine derivative which is a multiple of theamount which is effective when given 1-4 times per day.

The invention is illustrated, but not limited by the following Examplesin which the temperatures are in degrees Centigrade. The preparativethin layer chromatography has been carried out on Merck 60 F₂₅₄ plates.Unless otherwise stated the ammonia was concentrated aqueous ammonia ofspecific gravity 0.880.

EXAMPLE 1

A mixture of2-[3-(2,2,2-trifluoroethyl)thioureido]-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole(0.48 g.), saturated ethanolic ammonia (20 ml.) and yellow mercuricoxide (0.5 g.) was stirrred at room temperature for 3 hours and thenfiltered. The filtrate was evaporated to dryness, and the gummy residue(0.45 g.) converted to the hydrogen maleate salt which wasrecrystallised from ethanol to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazolehydrogen maleate, m.p. 159°-160° (decomp).

The2-[3-(2,2,2-trifluoroethyl)thioureido]-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazoleused as starting material may be obtained as follows:

A mixture of 2,2,2-trifluoroethyl isothiocyanate (0.68 g.) and2-amino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole (1.08g.) in dimethylformamide (5 ml.) was maintained at 60° for 4 hours andthen evaporated to dryness. The residue was recrystallised fromacetonitrile to give2-[3-(2,2,2-trifluoroethyl)thioureido]-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole,m.p. 157°-158°.

EXAMPLE 2

Methyl isothiocyanate (80 mg.) was added to2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(320 mg.) dissolved in methanol (5 ml.) and the solution kept at roomtemperature for 18 hours and then evaporated to dryness. The residualgum was purified by preparative thin layer chromatography using ethylacetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[2-(3-methylthioureido)ethylthiomethyl]thiazole(90 mg.), characterised as the hydrogen maleate, m.p. 137°139° (decomp.)(after crystallisation from acetonitrile.).

The2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleused as starting material may be obtained as follows:

A mixture of 2,2,2-trifluoroethylamine hydrochloride (4.07 g.),butan-1-ol (20 ml.) and sodium dicyanamide (2.7 g.) was heated underreflux with stirring for 6 hours. The hot solution was filtered and thefiltrate evaporated to dryness. The residual gum in a mixture of water(10 ml.) and concentrated hydrochloric acid (3.5 ml.) was stirredvigorously while adding thioacetamide (2.25 g.) in portions over 10minutes. The mixture was stirred at room temperature for 30 minutes,heated on the steam bath for 1 hour and then kept at room temperaturefor 16 hours. The mixture was washed with ethyl acetate and the aqueousphase basified with saturated aqueous potassium carbonate and thenextracted with ethyl acetate. The ethyl acetate extracts were dried andevaporated to dryness to give 2,2,2-trifluoroethylamidinothioureacharacterised as the hydrogen maleate, m.p. 164°-166°.

A mixture of 1,3-dichloroacetone (0.254 g.) and2,2,2-trifluoroethylamidinothiourea (0.4 g.) in acetone (10 ml.) wasstirred at room temperature for 16 hours and then evaporated to dryness.A solution of the residue in ethanol (5 ml.) was cooled to 0° andstirred while adding a mixture of 2-aminoethanethiol hydrochloride(0.227 g.) and sodium ethoxide (0.41 g.) in ethanol (10 ml.) over 5minutes. The mixture was allowed to warm to room temperature and stirredfor 1 hour, and then filtered. The filtrate was evaporated to drynessand the residue was treated with water (5 ml.) and the mixture extractedwith ethyl acetate (3×20 ml.). The combined ethyl acetate extracts weredried and evaporated to dryness to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleas a gum (0.55 g.) which was used without further purification.

EXAMPLE 3

Dimethyl(cyanoimido)dithiocarbonate (0.22 g.) was added to2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.47 g.) in ethanol (5 ml.) and the solution kept at room temperaturefor 18 hours. A 33% w/v solution of methylamine in ethanol (10 ml.) wasadded and the mixture stirred at room temperature for two hours and thenevaporated to dryness. The residual gum was purified by preparative thinlayer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/vas developing solvent to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole(0.2 g.) which was converted to the hydrogen maleate salt identical tothat described in Example 1.

EXAMPLE 4

The process described in Example 3 was repeated using4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutyl)pyrimidine inplace of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleand there was thus obtained4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(2-cyano-3-methylguanidino)butyl]pyrimidinehydrogen maleate, m.p. 129°-132°.

The 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutyl)pyrimidineused as starting material may be obtained as follows:

A solution of 5-phthalimidopentanenitrile (45.6 g.) and ethanol (9.2 g.)in dioxan (150 ml.) was cooled to 0° and saturated with HCl gas. Themixture was kept at 0° for 18 hours and then evaporated to dryness. Astirred solution of the residue in methanol (200 ml.) was treatedsuccessively with sodium methoxide (10.8 g.) and ammonium chloride (10.7g.) and the mixture stirred at room temperature for 18 hours and thenfiltered. The filtrate was evaporated to dryness and the residuetriturated with acetonitrile and filtered to give1-amidino-4-phthalimidobutane hydrochloride (47.5 g.), m.p. 175°-180°,which was used without further purification.

A solution of 2-chloroacrylonitrile (1.75 g.) in acetronitrile (10 ml.)was added over 15 minutes to an ice-cooled mixture of1-amidino-4-phthalimidobutane hydrochloride (5.64 g.), acetonitrile (50ml.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (6.08 g.). The mixture wasstirred for a further two hours and then evaporated to dryness. Theresidue was treated with water (50 ml.) and the mixture extracted withethyl acetate (2×50 ml.). The combined ethyl acetate extracts wereextracted with N hydrochloric acid (3×30 ml.) and the combined aqueousextracts neutralised with sodium bicarbonate and extracted with ethylacetate. The ethyl acetate extracts were evaporated to dryness and theresidue recrystallised from acetonitrile to give4-amino-2-(4-phthalimidobutyl)pyrimidine (2.5 g.), m.p. 139°-140°.

A mixture of 4-amino-2-(4-phthalimidobutyl)pyrimidine (1 g.),2,2,2-trifluoroethylisothiocyanate (1 g.) and acetonitrile was stirredat 70° for 18 hours. The mixture was diluted with acetonitrile (10 ml.),cooled in ice and then filtered to give4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(4-phthalimidobutyl)pyrimidine(1.03 g.), m.p. 204°-205°.

A mixture of4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(4-phthalimidobutyl)pyrimidine(1.02 g.), dimethyl formamide (5 ml.), ethanol (5 ml.), ammoniumchloride (0.134 g.), triethylamine (0.253 g.) and yellow mercuric oxide(0.8 g.) was stirred at room temperature for 18 hours and then filteredand the filtrate evaporated to dryness. Water was added to the residueand the mixture extracted with ethyl acetate, and the ethyl acetateextract evaporated to dryness.

A solution of the residue in ethanol (20 ml.) was treated with hydrazinehydrate (0.25 g.) and the mixture heated under reflux for 0.5 hours andthen evaporated to dryness. The residue was stirred with N hydrochloricacid and then filtered and the filtrate basified with 17N NaOH. Themixture was extracted with ethyl acetate, and the ethyl acetate extractsdried and evaporated to dryness to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutyl)pyrimidine as agum (0.62 g.) which was used without further purification.

EXAMPLE 5

The process described in Example 2 was repeated using4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutyl)pyrimidine inplace of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleand there was thus obtained4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[2-(3-methylthioureido)butyl]pyrimidinehydrogen maleate, m.p. 145°-146°.

EXAMPLE 6

To a solution of 2-[2-(2,2,2trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.5 g.) in methanol(15 ml.) was added dimethyl(cyanoimido)dithiocarbonate (0.29 g.) and thesolution was allowed to stand at room temperature for 3 hours. Theresidue obtained on evaporation of the solvent was subjected topreparative thin layer chromatography using chloroform/methanol/ammonia90:10:0.5 v/v/v for development. The appropriate zone of thechromatogram was isolated and extracted with hot ethanol/chloroform50:50 v/v (200 ml.). The residue (0.35 g.) obtained on evaporation ofthe solvent was dissolved in ethanol (2 ml.) and to this solution wasadded 33% w/v ethanolic methylamine (20 ml.). After standing overnightthe reaction mixture was evaporated to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-cyano-2-methylguanidino)butyl]thiazolea straw coloured glass-like material. The n.m.r. spectrum in d₆ dimethylsulphoxide using tetramethylsilane as internal standard included thefollowing resonances (δ): 2.7(3H, doublet), 4.1 (2H, multiplet) 6.4 (1H,singlet)--on addition of D₂ O the multiplet at δ4.1 collapsed to aquartet.

The 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole usedas starting material may be prepared as follows:

To a solution of N-(6-chloro-5-oxohexyl)phthalimide (3.4 g.) in ethanolwas added N-(2,2,2-trifluoroethylamidino)thiourea (2.75 g.) in ethanol(30 ml.). The mixture was heated under reflux for 2 hours and thereaction mixture concentrated to small volume by evaporation. Followingtreatment of the resulting solution with ether until the solution wasjust turbid, crystalline2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-phthalimidobutyl)thiazolehydrochloride (3.6 g.) was precipitated. This material (2.1 g.) inethanol (20 ml.) and water (5 ml.) was heated to boiling and thesolution pH was adjusted to 12 by addition of 2N sodium hydroxide. Afterheating on a steam bath for 10 minutes, the solution pH was adjusted to3 with conc. hydrochloric acid and heating continued for a further 0.5hour. The solution was cooled, adjusted to pH 12 with 2N sodiumhydroxide and extracted with ethyl acetate (2×30 ml.). Evaporation ofthe washed (H₂ O), dried (magnesium sulphate) extract gave2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole as a paleyellow gum which was used without further purification.

EXAMPLE 7

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.3 g.)and methyl isothiocyanate (0.18 g.) in methanol (6 ml.) was allowed tostand at room temperature for 3 hours. The residue obtained onevaporation of the solvent was subjected to preparative thin layerchromatography using chloroform/methanol/ammonia 90:10:0.5 v/v/v fordevelopment. The appropriate zone of the chromatogram was isolated andextracted with hot ethanol/chloroform 50:50 v/v (100 ml.). Evaporationof the solvent gave2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-methylthioureido)butyl]thiazoleas a straw-coloured gum. The n.m.r. spectrum d₆ dimethylsulphoxide usingtetramethylsilane as internal standard included the following resonances(δ): 2.75 (3H, doublet), 4.04 (2H, multiplet) and 6.34 (1H, singlet). Onaddition of D₂ O the multiplet at δ4.04 collapsed to a quartet.

EXAMPLE 8

To a solution of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.75 g.)in acetonitrile (12 ml.) was added 1,1-di(methylthio)-2-nitroethylene(0.43 g.) in warm acetonitrile (8 ml.) and the mixture was allowed tostand at room temperature overnight. The residue obtained on evaporationof the solvent was subjected to preparative thin layer chromatographyusing chloroform/methanol 88:12 v/v for development. The appropriatezone of the chromatogram was isolated and extracted with hotethanol/chloroform 50:50 v/v (200 ml.) and the residue crystallised fromethanol to give1-[4-(2-[(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]-1-methylthio-2-nitroethylene,m.p. 140°-141°.

EXAMPLE 9

To a solution of1-[4-(2-[(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]-1-methylthio-2-nitroethylene(10.3 g.) in warm methanol was added an excess of ethanolic methylamine(33% w/v) (20 ml.) and the mixture allowed to stand at room temperatureovernight. Evaporation of the solvent and crystallisation of the residuefrom methanol gave1-[4-(2-[(2,2,2-trifluoroethyl)guanidinothiazol-4-yl)butylamino]-1-methylamino-2-nitroethylene(0.22 g.), m.p. 83°-86° (with effervescence).

EXAMPLE 10

To a solution of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.5 g.)in ethanol (10 ml.) was addeddimethyl(methylsulphonylimido)dithiocarbonate (0.35 g.) in ethanol (10ml.) and the mixture was allowed to stand at room temperature overnight.The residue obtained on evaporation of the solvent was subjected topreparative thin layer chromatography using chloroform/methanol 90:10v/v for development. The appropriate zone as the chromatogram wasisolated and extracted with hot ethanol/chloroform 50:50 v/v (200 ml.).Evaporation of the solvent gave a gum (0.5 g.) This gum (0.17 g.) wasdissolved in acetone/methanol 1:10 v/v (0.5 ml.). To this solution wasadded an excess of maleic acid in acetone/ether 50:50 v/v to precipitate2-(2,2,2-trifluoroethyl)guanidino-4-[4-(3-methylsulphonyl-2-methylisothioureido)butyl]thiazolehydrogen maleate, m.p. 164°-166° (decomp.).

EXAMPLE 11

To a solution of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-methylsulphonyl-2-methylisothioureido)butyl]thiazole(0.33 g.) in ethanol (10 ml.) was added ethanolic methylamine (33% w/v)(25 ml.) and the mixture allowed to stand at room temperature for 48hours. The residue obtained on evaporation of the solvent was dissolvedin methanol (0.5 ml.) and to this solution was added an excess of maleicacid in ether to precipitate2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(2-methylsulphonyl-3-methylguanidino)butyl]thiazoleas a white powder, m.p. 93°-95°, which contained 1.5 moles of maleicacid.

EXAMPLE 12

2-[2-(2,2,2-Trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole wasconverted to the dihydrochloride by treatment with methanolic hydrogenchloride. This hydrochloride (0.4 g.) in n-butanol (50 ml.) was treatedwith sodium dicyanimide (0.11 g.) and the mixture heated under refluxfor 14 hours during which time further additions (totalling 0.1 g.) ofsodium dicyanimide were made. The residue obtained on evaporation of thesolvent was partitioned between 0.1N sodium hydroxide (20 ml.) and ethylacetate (60 ml.). Evaporation of the water-washed and dried (magnesiumsulphate)ethyl acetate extract gave a gum which was subjected topreparative thin layer chromatography using ethyl acetate/methanol/water6:1:1 v/v/v for development. The appropriate zone of the chromatogramwas isolated and extracted with hot ethanol/chloroform 50:50 v/v (200ml.). The residue obtained on evaporation of the solvent was dissolvedin acetone (2 ml.) and to this solution was added an excess of maleicacid in acetone/ether 50:50 v/v followed by ether until precipitationbegan, to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(2-cyanoguanidino)butyl]thiazoleas a pale brown powder, m.p. 149°-156° (decomp.), which contained maleicacid 1.75 moles and water of crystallisation 0.5 mole.

EXAMPLE 13

To a solution of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(3-aminopropyl)thiazole (0.2 g.)in ethanol (10 ml.) was added methyl isothiocyanate (0.2 g.) and themixture heated under reflux for 2 hours. The residue obtained onevaporation of the solvent was subjected to preparative thin layerchromatography using chloroform/methanol/ammonia 90:10:0.5 v/v/v fordevelopment. The appropriate zone of the chromatogram was isolated andextracted with hot ethanol/chloroform 50:50 v/v (200 ml.). The residueobtained by evaporation of the solvent was dissolved in methanol (0.5ml.) and to this solution was added an excess of maleic acid inacetone/ether 50:50 v/v followed by ether until precipitation began.There was thus isolated2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[3-(3-methylthioureido)propyl]thiazolehydrogen maleate, m.p. 150°-156° (decomp.).

The 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(3-aminopropyl)thiazole usedas starting material may be prepared by a procedure exactly analogous tothat described in Example 6 for2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole exceptthat N-(5-chloro-4-oxopentyl)phthalimide is used in place ofN-(6-chloro-5-oxohexyl)phthalimide.

EXAMPLE 14

An intimate mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.39 g.)and 5-(4-chlorobenzyl)-2-methylthiopyrimid-4-one (0.39 g.) was heated at150°-160° for 20 min. during which time effervescence occurred. Theresidue obtained on cooling was subjected to preparative thin layerchromatography using chloroform/methanol/ammonia 90:10:0.5 v/v/v fordevelopment. The appropriate zone of the chromatogram was isolated andextracted with hot ethanol/chloroform (50:50 v/v; 200 ml.). Evaporationof the eluate gave a glass which was dissolved in acetone (0.3 ml.) andtreated with an excess of a saturated solution of maleic acid in acetoneto give a maleate salt of5-(4-chlorobenzyl)-2-{4-[2-(2,2,2-trifluoroethyl)guanidinothiazol-4-yl]butylamino}pyrimid-4-oneas a white powder (0.1 g.) which contained 1.5 moles of maleic acid and1.5 moles of water of crystallisation. The n.m.r. spectrum in d₆dimethylsulphoxide using tetramethylsilane (δ=0) as internal standardincluded the following resonances (δ): 3.45 (2H, singlet); 4.1 (2H,multiplet); 7.1 (3H, singlet--maleic acid); 7.45 (1H, singlet) and 8.2(4H, singlet).

The 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole usedas starting material may be prepared as follows:

To a solution of N-(6-chloro-5-oxyhexyl)phthalimide (3.4 g.) in ethanolwas added N-(2,2,2-trifluoroethylamidino)thiourea (2.75 g.) in ethanol(30 ml). The mixture was heated under reflux for 2 hours and thereaction mixture concentrated to small volume by evaporation. Followingtreatment of the resulting solution with ether until the solution wasjust turbid, crystalline2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-phthalimidobutyl)thiazolehydrochloride (3.6 g.) was precipitated. This material (2.1 g.) inethanol (20 ml.) and water (5 ml.) was heated to boiling and thesolution pH was adjusted to 12 by addition of 2N sodium hydroxide. Afterheating on a steam bath for 10 minutes, the solution pH was adjusted to3 with conc. hydrochloric acid and heating continued for a further 0.5hour. The solution was cooled, adjusted to pH 12 with 2N sodiumhydroxide and extracted with ethyl acetate (2×30 ml.). Evaporation ofthe washed (H₂ O), dried (magnesium sulphate) extract gave2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole as a paleyellow gum which was used without further purification.

EXAMPLE 15

An intimate mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.6 g.)and 3-methylthio-6-(3-methoxybenzyl)-1,2,4-triazine-5-one (0.6 g.) washeated at 160° for 20 min. during which time effervescence occurred. Theresidue obtained on cooling was triturated with hot methanol (20 ml.)and the precipitate formed on cooling was collected and suspended in hotmethanol (15 ml.). To this suspension was added an excess of a solutionof maleic acid in acetone whereupon a clear solution was obtained. Thecooled solution was treated with ether until turbid. On standing a solidprecipitated. This solid was collected and dissolved in hot methanol anddecolourised with charcoal. Addition of ether to the clarifiedmethanolic solution precipitated a maleate salt of6-(3-methoxybenzyl)-3-{2-[2-(2,2,2-trifluoroethyl)guanidinothiazol-4-yl]butylamino}-1,2,4-triazin-5-one,which was obtained as a fawn powder (0.1 g.) which contained one mole ofmaleic acid and 3 moles of water of crystallisation. The n.m.r. spectrumin d₆ dimethylsulphoxide using tetramethylsilane as internal standard(δ=0) included the following resonances (δ): 3.7 (2H, singlet+3H,singlet); 4.1 (2H, multiplet); 7.1 (2H, singlet-maleic acid); 7.45 (1H,singlet); and 7.75 (3H, multiplet).

EXAMPLE 16

A solution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(3-amino)propylthio]pyrimidine(180 mg.) in acetonitrile (2 ml.) was treated withdimethyl(cyanoimidio)dithiocarbonate (85 mg.) and the solution stood atroom temperature for 18 hours. The crystalline solid which precipitatedwas collected to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(3-cyano-2-methylisothioureido)propylthio]pyrimidine(175 mg.), m.p. 189°-190°.

The4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(3-amino)propylthio]pyrimidineused as starting material may be prepared as follows:

A mixture of thiocytosine (248 mg.), 1,5-diazabicyclo[5,4,0]undec-5-ene(300 mg.), ethanol (10 ml.) and N-3-bromopropylphthalimide (536 mg.) wasstirred at room temperature for 2 hours and then evaporated to dryness.The residue was partitioned between water and ethyl acetate, and theethyl acetate extract dried and evaporated to dryness. A mixture of theresidue (700 mg.), acetonitrile (3 ml.) and2,2,2-trifluoroethylisothiocyanate (420 mg.) was stirred at 70° for 18hours then cooled and filtered to give4-[3-(2,2,2-trifluoroethyl)thioureido]-2-[(3-phthalimido)propylthio]pyrimidine(480 mg.), m.p. 214°-215° after recrystallisation from a mixture ofethanol and N,N-dimethylformamide.

A mixture of4-[3-(2,2,2-trifluoroethyl)thioureido]-[(3-phthalimido)propylthio]pyrimidine(0.4 g.), N,N,-dimethylformamide (5 ml.), saturated ethanolic ammonia(10 ml.) and yellow mercuric oxide (280 mg.) was stirred at roomtemperature for 3 hours and then filtered and the filtrate evaporated todryness. A solution of the residue in ethanol (10 ml.) was treated withhydrazine hydrate (1 ml.), the mixture heated under reflux for 1 hourand then evaporated to dryness. The residue was stirred with 1Nhydrochloric acid and then filtered and the filtrate basified with 17NNaOH. The mixture was extracted with ether and the combined etherextracts dried and evaporated to dryness to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(3-amino)propylthio]pyrimidinewhich was used without further purification.

EXAMPLE 17

A solution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-cyano-2-methylsiothioureido)propylthio]pyrimidine(140 mg.) in 33% w/v ethanolic methylamine (5 ml.) was allowed to standat room temperature for 4 hours. The solution was evaporated to drynessand the residue recrystallised from ethyl acetate to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-cyano-3-methylguanidino)propylthio]pyrimidine(105 mg.), m.p. 159°-160°.

EXAMPLE 18

2,2,2-Trifluoroethylisothiocyanate (0.31 g.) was added to a solution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutyl)pyrimidine (0.58g.) in acetonitrile (5 ml.), and the solution kept at room temperaturefor 18 hours and then evaporated to dryness. The residual gum waspurified by preparative thin layer chromatography using ethylacetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(3-(2,2,2-trifluoroethyl)thioureido)butyl]pyrimidine(0.22 g.) characterised as the hydrogen maleate, m.p. 142°-145° (afterrecrystallisation from acetonitrile).

By a similar process, using the appropriate isothiocyanate in place of2,2,2-trifluoroethylisothiocyanate there were obtained4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(3-methoxycarbonylthioureido)butyl]pyrimidinehydrogen maleate, m.p. 168°-169° (decomp.), and4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(3-phenylthioureido)butyl]pyrimidine,m.p. 124°-127°.

EXAMPLE 19

Dimethyl(cyanoimido)dithiocarbonate (0.33 g.) was added to a solution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutyl)pyrimidine (0.66g.) in acetonitrile (5 ml.) and the solution kept at room temperaturefor 18 hours and then evaporated to dryness. The residue was trituratedwith a small volume of acetonitrile and then filtered to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(3-cyano-2-methylisothioureido)butyl]pyrimidine,m.p. 164°-166°.

EXAMPLE 20

A solution of dimethyl(methanesulphonylimido)dithiocarbonate (0.2 g.) inacetonitrile (5 ml.) was added to a solution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutyl)pyrimidine (0.29g.) in a acetonitrile (2 ml.) and the solution left at room temperaturefor 18 hours and then evaporated to dryness. The residue was dissolvedin a 33% w/v solution of methylamine in ethanol (5 ml.), and thesolution kept at room temperature for 18 hours and then evaporated todryness. A solution of the residue in ethyl acetate was added to asolution of maleic acid in acetone and the precipitate collected andrecrystallised from acetonitrile to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(3-methylsulphonyl-2-methylguanidino)butyl]pyrimidinehydrogen maleate (0.25 g.), m.p. 162°-165°.

By a similar process, using 1,1-bis(methylthio)-2-nitroethylene in placeof dimethyl(methanesulphonylimido)dithiocarbonate, there was obtained1-[4-(2-[(2,2,2-trifluoroethyl)guanidino]pyrimid-2-yl)butylamino]-1-methylamino-2-nitroethylenehydrogen maleate, m.p. 167°-169°.

EXAMPLE 21

1-Nitro-2-methylisothiourea (0.135 g.) was added to a stirred solutionof4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-aminoethyl)thiomethyl]pyrimidine(0.31 g.) in acetonitrile (5 ml.) and the suspension stirred at roomtemperature for 2 hours. The insoluble material was collected to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[2-(2-nitro-3-methylguanidino)ethylthiomethyl]pyrimidine(0.35 g.) m.p. 199°-200° (decomp.)

The4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-aminoethyl)thiomethyl]pyrimidineused as starting material may be obtained as follows:

Solutions of 2-chloroacryloitrile (15.7 g.) in acetronitrile (20 ml.)and 1,5-diazabicyclo[5,4,0]undec-5-ene (27 g.) in acetonitrile (20 ml.)were added simultaneously over 30 minutes to a stirred, ice-cooledsolution of 2-chloroacetamidine hydrochloride (19.2 g.) and1,5-diazabicyclo[5,4,0]undec-5-ene (22.5 g.) in acetonitrile (200 ml.),keeping the temperature below 30° and the mixture stirred a further 4hours at room temperature after the addition was complete. The resultingmixture was stirred with a mixture of water (100 ml.) and ethyl acetate(200 ml.) and then filtered through a pad of diatomaceous earth and theethyl acetate phase separated. The aqueous phase was further extractedwith ethyl acetate (2×100 ml.) and the combined ethyl acetate extractsdried and evaporated to dryness to give 4-amino-2-chloromethylpyrimidine(14.5 g.) which was used without further purification.

A solution of 4-amino-2-chloromethylpyrimidine (11.6 g.) in methanol (20ml.) was added over 15 minutes to a stirred mixture of sodium methoxide(4.32 g.), N-(2-mercaptoethyl)phthalimide (16.6 g.) and methanol (100ml.), and the mixture stirred for 1 hour after the addition was completeand then evaporated to dryness. The residue was partitioned between 1Nhydrochloric acid and ethyl acetate, and the aqueous phase separated andneutralised by the addition of sodium bicarbonate. The mixture wasextracted with ethyl acetate and the extracts dried and evaporated todryness, and the residue was recrystallised from acetonitrile to give4-amino-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine, m.p. 131°-133°.

A mixture of 4-amino-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine (5.9g.), 2,2,2-trifluoroethylisothiocyanate (3.9 g.) and acetonitrile (20ml.) was stirred at 70° for 72 hours. The reaction mixture was cooledand the crystalline precipitate collected to give4-[3-(2,2,2-trifluoroethyl)thioureido]-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine(5.35 g.), m.p. 178°-179°.

A mixture of4-[3-(2,2,2-trifluoroethyl)thioureido]-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine(6.8 g.), dimethylformamide (30 ml.), saturated ethanolic ammonia (5ml.) and yellow mercuric oxide (6.5 g.) was stirred at room temperaturefor 2 hours and then filtered. The filtrate was evaporated to drynessand the residue triturated with ether and filtered to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine(5.6 g.), m.p. 167°-168° after crystallisation from ethanol.

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine(5.4 g.), ethanol (30 ml.) and 99% hydrazine hydrate (3 ml.) was heatedunder reflux for 1 hour and then evaporated to dryness. The residue wasstirred with N hydrochloric acid and then filtered and the filtratebasified with 17N NaOH. The mixture was extracted with ether, and theether extracts dried and evaporated to dryness to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-aminoethyl)thiomethyl]pyrimidine(2.93 g.) which was used without further purification.

EXAMPLE 22

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-aminoethyl)thiomethyl]pyrimidine(0.31 g.) 1-methylamino-1-methylthio-2-nitroethylene (0.15 g.) andacetonitrile (5 ml.) was heated under reflux for 6 hours and then leftat room temperature for 18 hours. The yellow crystalline precipitate wascollected to give1-(2-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]ethylamino)-1-methylamino-2-nitroethylene(0.26 g.), m.p. 154°-157° after recrystallisation from ethanol.

By a similar process using2,2-biscyano-1-methylamino-1-methylthioethylene in place of1-methylamino-1-methylthio-2-nitroethylene there was obtained1-(2-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]ethylamino)-2,2-biscyano-1-methylaminoethylene,m.p. 173°-174°.

EXAMPLE 23

A solution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-aminoethyl)thiomethyl]pyrimidine(0.33 g.) and dimethyl(cyanoimido)dithiocarbonate (0.17 g.) inacetonitrile was left at room temperature for 18 hours and thenevaporated to dryness. The residue was dissolved in ethanol (5 ml.), thesolution treated with 99% hydrazine hydrate (0.2 ml.), the mixtureallowed to stand at room temperature for 0.5 hours and then evaporatedto dryness. The residue was triturated with water and filtered to give3-amino-5-(2-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]ethylamino)-1H-1,2,4-triazole(0.17 g.), m.p. 199°-201° after recrystallisation from a mixture ofmethanol and acetonitrile.

EXAMPLE 24

A solution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-aminoethyl)thiomethyl]pyrimidine(0.15 g.) and dimethyl(methanesulphonylimido)dithiocarbonate (0.1 g.) inacetonitrile (2 ml.) was left at room temperature for 4 hours and thenevaporated to dryness. The residue was dissolved in 33% w/v methylaminein ethanol and the solution left at room temperature for 18 hours andthen evaporated to dryness. The residue was purified by preparative thinlayer chromatography using chloroform/methanol/ammonia 8:2:0.2 v/v/v asdeveloping solvent to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[2-(2-methanesulphonyl-3-methylguanidino)ethylthiomethyl]pyrimidine(0.09 g.) characterised as the hydrogen maleate, m.p. 148°-149° afterrecrystallisation from acetonitrile.

EXAMPLE 25

A mixture of4-amino-2-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]pyrimidine (0.5g.), 2,2,2-trifluoroethylisothiocyanate (0.55 g.) and pyridine (10 ml.)was heated at 70° for 18 hours and then evaporated to dryness. Theresidue was dissolved in ethyl acetate and the solution washed with 2Naqueous acetic acid, dried and evaporated to dryness. The residue wasdissolved in ethanolic ammonia (15 ml.), treated with yellow mercuricoxide (0.4 g.) and the mixture stirred at room temperature for 4 hours.The mixture was filtered and the filtrate evaporated to dryness. Theresidue was purified by preparative thin layer chromatography usingethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent togive4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[2-(3-cyano-2-methylguanidino)ethylthiomethyl]pyrimidine(0.2 g.) characterised as the hydrogen maleate, m.p. 111°-114° (decomp.)after recrystallisation from acetonitrile.

The 4-amino-2-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]pyrimidineused as starting material may be obtained as follows:

2-Aminoethanethiol hydrochloride (2.02 g.) and4-amino-2-chloromethylpyrimidine hydrogen maleate (2.3 g.) were added toa solution of sodium (1.23 g.) in methanol (25 ml.) and the mixturestirred at room temperature for 18 hours and then evaporated to dryness.The residue was dissolved in water, and the solution extracted fourtimes with ethyl acetate and the combined ethyl acetate extracts driedand evaporated to dryness. The residue was dissolved in acetonitrile (6ml.), the solution treated with dimethyl(cyanoimido)dithiocarbonate(1.04 g.) and the mixture left at room temperature for 18 hours. Themixture was filtered to give4-amino-2-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]pyrimidine(0.86 g.), m.p. 112°-114°.

A solution of4-amino-2-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]pyrimidine(0.75 g.) in 33% w/v methylamine in ethanol (15 ml.) was left at roomtemperature for 18 hours. The solution was concentrated to 5 ml., cooledin ice, and the crystalline precipitate collected to give4-amino-2-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]pyrimidine (0.52g.), m.p. 189°-190°.

EXAMPLE 26

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutyl)pyrimidine (0.15g.), 1-methyl-3-trifluoromethanesulphonylthiourea (0.11 g.), ethanol (10ml.) and yellow mercuric oxide (0.22 g.) was stirred at room temperaturefor 18 hours. The mixture was filtered and the filtrate evaporated todryness. The residue was dissolved in ethyl acetate and the solutionadded to a solution of maleic acid in acetone. The precipitated solid(130 mg.) was collected and recrystallised from ethyl acetate to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(3-methyl-2-trifluoromethanesulphonylguanidino)butyl]pyrimidinehydrogen maleate, m.p. 156°-157°.

The 1-methyl-3-trifluoromethanesulphonylthiourea used as startingmaterial may be obtained as follows:

A solution of methylisothiocyanate (0.21 g.) in acetone (10 ml.) wasadded to a solution of trifluoromethanesulphonamide (0.45 g.) and sodiumhydroxide (0.12 g.) in water (5 ml.), the mixture stirred at 60° for 18hours and then evaporated to dryness. The residue was dissolved in waterand the solution washed with ethyl acetate and then adjusted to pH 1with concentrated hydrochloric acid. The mixture was treated withcharcoal and filtered and the filtrate extracted with ethyl acetate. Thecombined ethyl acetate extracts were dried and evaporated to dryness andthe residue recrystallized from petroleum ether (b.p. 60°-80°) to give1-methyl-3-trifluoromethanesulphonylthiourea (0.27 g.), m.p. 88°-90°.

EXAMPLE 27

Dimethyl(cyanoimido)dithiocarbonate (0.08 g.) was added to a solution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutylthio)pyrimidine(0.17 g.) in acetonitrile (2 ml.) and the solution left at roomtemperature for 18 hours and then evaporated to dryness to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(3-cyano-2-methylisothioureido)butylthio]pyrimidine,characterised as the hydrogen maleate m.p. 181°-183°.

The 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-aminobutylthio]pyrimidineused as starting material may be prepared as follows:

A mixture of 2-thiocytosine (0.25 g.),1,5-diazabicyclo[5,4,0]undec-5-ene (0.33 g.), ethanol (10 ml.) andN-(4-bromobutyl)phthalimide (0.62 g.) was stirred at room temperaturefor 18 hours and then evaporated to dryness. The residue was partitionedbetween water and ethyl acetate and the ethyl acetate phase was driedand evaporated to dryness. The residue was recrystallised fromacetonitrile to give 4-amino-2-(4-phthalimidobutylthio)pyrimidine (0.56g.), m.p. 164°-167°.

A mixture of 4-amino-2-(4-phthalimidobutylthio)pyrimidine (0.49 g.),acetonitrile (5 ml.) and 2,2,2-trifluoroethylisothiocyanate (0.28 g.)was stirred at 70° for 48 hours. A further 0.28 g. of2,2,2-trifluoroethylisothiocyanate was added and the mixture stirred at70° for 48 hours. The reaction mixture was cooled and filtered, theresidue stirred with N aqueous acetic acid and the undissolved solidcollected to give4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(4-phthalimidobutylthio)pyrimidine(0.49 g.), m.p. 201°-202° after recrystallisation from a mixture ofethanol and dimethylformamide.

A mixture of4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(4-phthalimidobutyl)pyrimidine(0.45 g.), dimethylformamide (20 ml.), saturated ethanolic ammonia (2ml.) and yellow mercuric oxide (0.32 g.) was stirred at room temperaturefor 5 hours, filtered and the filtrate evaporated to dryness. Asuspension of the residue (0.35 g.) in ethanol (20 ml.) was treated with99% hydrazine hydrate (1 ml.) and the mixture heated under reflux for 1hour and then evaporated to dryness. The residue was stirred with 2Nhydrochloric acid and filtered, and the filtrate basified with 17N NaOHand then extracted four times with ether. The combined ether extractswere dried and evaporated to dryness to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutylthio)pyrimidine(0.17 g.) which was used without further purification.

EXAMPLE 28

A solution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(3-cyano-2-methylisothioureido)butylthio]pyrimidine(0.17 g.) in 33% w/v methylamine in ethanol was left at room temperaturefor 18 hours and then evaporated to dryness. The residue was trituratedwith ether and the insoluble solid collected and recrystallised fromethyl acetate to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(2-cyano-3-methylguanidino)butylthio]pyrimidine,m.p. 179°-180°.

EXAMPLE 29

A solution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylthio)pyrimidine(0.31 g.) in acetonitrile (5 ml.) was treated with1-methylamino-1-methylthio-2-nitroethylene (0.15 g.) and the mixtureheated under reflux for 18 hours. The hot solution was filtered andcooled and the solid which crystallised was collected and recrystallisedfrom ethanol to give1-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-ylthio)propylamino]-1-methylamino-2-nitroethylene(0.11 g.), m.p. 189°-191°.

EXAMPLE 30

Dimethyl(methanesulphonylimido)dithiocarbonate (0.4 g.) was added to asolution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylthio)pyrimidine(0.62 g.) in ethanol (10 ml.) and the solution left at room temperaturefor 18 hours and then filtered. The filtrate was evaporated to dryness,the residue dissolved in 33% w/v methylamine in ethanol (10 ml.), thesolution left at room temperature for 18 hours and then evaporated todryness. The residue was partitioned between water and ethyl acetate,and the ethyl acetate phase was separated, dried and evaporated todryness. A solution of the residue in ethyl acetate was added to asolution of maleic acid in acetone and the crystalline precipitatecollected to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-methanesulphonyl-3-methylguanidino)propylthio]pyrimidinehydrogen maleate (0.8 g.), m.p. 162°-164°.

EXAMPLE 31

A mixture of2,4-diamino-6-[5-(2-methanesulphonyl-3-methylguanidino)pentyl]-1,3,5-triazine(0.4 g.), 2,2,2-trifluoroethylisothiocyanate (0.4 g.) anddimethylformamide (0.5 ml.) was heated at 120° for 1 hour and then at60° for 18 hours. The mixture was evaporated to dryness, the residuepartitioned between water and ethyl acetate, and the ethyl phase wasseparated, dried, and evaporated to dryness. The residue was dissolvedin saturated ethanolic ammonia (10 ml.) and the solution treated withyellow mercuric oxide (0.5 g.). The mixture was stirred at roomtemperature for 18 hours, filtered and the filtrate evaporated todryness. The residue was purified by chromatography using ethylacetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give2-amino-4-[2-(2,2,2-trifluoroethyl)guanidino]-6-[5-(2-methanesulphonyl-3-methylguanidino)pentyl]-1,3,5-triazine(0.07 g.) characterised as the bishydrogen maleate, m.p. 131°-133° afterrecrystallisation from acetone.

The2,4-diamino-6-[5-(2-methanesulphonyl-3-methylguanidino)pentyl]-1,3,5-triazineused as starting material in the above process may be prepared asfollows:

A mixture of biguanide (1.05 g.),4,5,6,7-tetrahydro-2-methoxy-3H-azepine (1.27 g.) and ethanol (50 ml.)was heated under reflux for 18 hours, cooled and the solid thatcrystallised was collected to give2,4-diamino-6-(5-aminopentyl)-1,3,5-triazine which was used withoutfurther purification.

2,4-Diamino-6-(5-aminopentyl)-1,3,5-triazine (0.39 g.) was added to asolution of dimethyl(methanesulphonylimido)dithiocarbonate (0.4 g.) inmethanol (5 ml.) and the solution left at room temperature for 2 hours.The solution was treated with 33% w/v methylamine in ethanol (5 ml.) andthe solution stirred at room temperature for 24 hours. The crystallinesolid which had separated was collected to give2,4-diamino-6-[5-(2-methanesulphonyl-3-methylguanidino)pentyl]-1,3,5-triazine,m.p. 194°-195°.

EXAMPLE 32

Dimethyl(cyanoimido)dithiocarbonate (0.12 g.) was added to a solution of2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(2-aminoethylthiomethyl)pyridine(0.23 g.) in acetonitrile (5 ml.) and the solution left at roomtemperature for 18 hours and then evaporated to dryness. The residue wasdissolved in 33% w/v methylamine in ethanol (5 ml.) and the solutionleft at room temperature for 18 hours and then evaporated to dryness.The residue was purified by preparative thin layer chromatography usingethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as the developing solventto give2-[2-(2,2,2-trifluoroethyl)guanidino]-6-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]pyridine(0.12 g.) characterised as the hydrogen maleate, m.p. 137°-140° afterrecrystallisation from acetone.

The2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(2-aminoethylthiomethyl)pyridineused as starting material in the above process may be prepared asfollows:

A mixture of 6-aminopyridine-2-carboxylic acid (5.0 g.) and a 1.35Msolution of borane in tetrahydrofuran (100 ml.) was stirred under argonat reflux for 48 hours. The mixture was cooled and treated with 2N NaOH(50 ml.) and the mixture stirred at room temperature for 18 hours. Theaqueous phase was saturated with sodium chloride and the organic phaseseparated. The aqueous phase was extracted twice with ethyl acetate andthe ethyl acetate extracts combined with the tetrahydrofuran solutionand the whole evaporated to dryness. The residue was dissolved in ethylacetate (100 ml.) and the solution washed with saturated aqueous sodiumchloride solution (5 ml.) and then dried and evaporated to dryness togive crude 2-amino-6-hydroxymethylpyridine (2.3 g.) which was usedwithout further purification.

2,2,2-Trifluoroethylisothiocyanate (2.82 g.) was added to a solution of2-amino-6-hydroxymethylpyridine (2.1 g.) in acetonitrile (20 ml.) andthe solution kept at room temperature for 18 hours and then evaporatedto dryness. The residue was partitioned between ethyl acetate and waterand the ethyl acetate phase separated, dried and evaporated to dryness.The residue was recrystallised from ethanol to give2-[3-(2,2,2-trifluoroethyl)thioureido]-6-[N-(2,2,2-trifluoroethyl)thiocarbamoyloxymethyl]pyridine(0.8 g.), m.p. 173°-175°.

A mixture of2-[3-(2,2,2-trifluoroethyl)thioureido]-6-[N-(2,2,2-trifluoroethyl)thiocarbamoyloxymethyl]pyridine(0.73 g.), dimethylformamide (20 ml.), saturated ethanolic ammonia (5ml.) and yellow mercuric oxide was stirred at room temperature for 18hours. The mixture was filtered and the filtrate evaporated to dryness.The residue was dissolved in concentrated aqueous ammonia (20 ml.), thesolution heated at 90° for 2 hours, and then evaporated to dryness. Theresidue was partitioned between N aqueous acetic acid and ether, and theaqueous phase separated and basified with 17N NaOH. The mixture wasextracted with ethyl acetate and the ethyl acetate extract dried andevaporated to dryness to give2-[2-(2,2,2-trifluoroethyl)guanidino]-6-hydroxymethylpyridine which wasused without further purification.

Thionyl chloride (0.2 ml.) was added to a solution of2-[2-(2,2,2-trifluoroethyl)guanidino]-6-hydroxymethylpyridine (0.2 g.)in tetrahydrofuran (5 ml.) and the mixture was left at room temperaturefor 0.5 hours and then evaporated to dryness. A solution of the residuein methanol (2 ml.) was added to a mixture of 2-aminoethanethiolhydrochloride (0.14 g.), sodium methoxide (0.22 g.) and methanol (15ml.), the mixture stirred at room temperature for 18 hours and thenevaporated to dryness. The residue was partitioned between N aqueousacetic acid and ether, and the aqueous phase separated and basified with17N NaOH. The mixture was extracted three times with ether to give2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(2-aminoethylthiomethyl)pyridinewhich was used without further purification.

EXAMPLE 33

A solution of bromine (0.064 g.) in methylene chloride (2 ml.) was addeddropwise over 15 minutes to a stirred solution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-methylsulphonyl-3-methylguanidino)propylthio]pyrimidine(0.176 g.) and pyridine (0.2 ml.) in methylene chloride (10 ml.), andthe mixture stirred at room temperature for one hour. The solution wasevaporated to dryness, and the residue purified by preparative thinlayer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/vas developing solvent to give5-bromo-4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-methylsulphonyl-3-methylguanidino)propylthio]pyrimidine(0.12 g.), m.p. 166°-167° after recrystallisation from ethanol.

EXAMPLE 34

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylamino)pyrimidine(0.097 g.), methanol (2 ml.) and 3-nitro-2-methylisothiourea (0.045 g.)was stirred at room temperature for 3 hours and then evaporated todryness. The residue was stirred with a mixture of ether and water, andthe insoluble material collected and dissolved in ethyl acetate. Thesolution was added to a solution of maleic acid in acetone, and thecrystalline precipitate collected to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-nitroguanidino)propylamino]pyrimidinebis hydrogen maleate (0.09 g.), m.p. 173°-174°.

The4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylamino)pyrimdineused as starting material in the above process may be obtained asfollows:

A mixture of 4-amino-2-methylthiopyrimidine (2.1 g.),2,2,2-trifluoroethylisothiocyanate (2.8 g.) and acetonitrile (5 ml.) wasstirred at 70° for 72 hours and then cooled, and the solid thatcrystallised was collected to give4-[3-(2,2,2-trifluoroethyl)thioureido]-2-methylthiopyrimidine (2.15 g.)which was used without further purification.

A mixture of4-[3-(2,2,2-trifluoroethyl)thioureido]-2-methylthiopyrimidine (2.15 g.),methanol (100 ml.), saturated ethanolic ammonia (10 ml.) and yellowmercuric oxide (4.3 g.) was stirred at room temperature for 2 hours andthen filtered. The filtrate was evaporated to dryness and the residuerecrystallised from ethanol to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-methylthiopyrimidine (1.5 g.),m.p. 201°-202°.

3-Chloroperbenzoic acid (0.8 g.) was added to a solution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-methylthiopyrimidine (0.5 g.) inethanol (50 ml.) and the solution left at room temperature for 18 hoursand then evaporated to dryness. The residue was dissolved in ethylacetate, the solution washed with aqueous potassium carbonate solutionand then dried and evaporated to dryness to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-methylsulphinylpyrimidine (0.5g.) which was used without further purification.

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-methylsulphinylpyrimidine (0.3g.) and 1,3-diaminopropane (1 ml.) was heated to 90° for 3 hours. Themixture was evaporated to dryness and the residue taken up in 2N aqueousacetic acid. The solution was washed with ether, basified with 17N NaOHand the mixture extracted five times with ether. The combined etherextracts were dried and evaporated to dryness to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylamino)pyrimidine(0.27 g.) which was characterised as the tris hydrogen maleate, m.p.159° after recrystallisation from acetone.

EXAMPLE 35

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylamino)pyrimidine(0.15 g.), dimethyl(methanesulphonylimido)dithiocarbonate (0.1 g.) andmethanol (2 ml.) was left at room temperature for 3 hours. A 33% w/vsolution of methylamine in ethanol (5 ml.) was added and the mixtureleft at room temperature for 18 hours and then evaporated to dryness.The residue was dissolved in acetone, the solution added to a solutionof maleic acid in acetone and the crystalline precipitate collected togive4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-methanesulphonyl-3-methylguanidino)aminopropylamino]pyrimidinebis hydrogen maleate (0.14 g.), m.p. 160°-161°.

EXAMPLE 36

A solution of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropyloxy)pyrimidine(0.07 g.) and dimethyl(cyanoimido)dithiocarbonate (0.035 g.) in ethanolwas left at room temperature for 2 hours. A 33% w/v solution ofmethylamino in ethanol (5 ml.) was added, the mixture left at roomtemperature for 18 hours and then evaporated to dryness. The residue wasdissolved in ethyl acetate and the solution added to a solution ofmaleic acid in acetone, and the crystalline precipitate collected togive4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-cyano-3-methylguanidino)propyloxy]pyrimidinehydrogen maleate (0.085 g.), m.p. 146°-148°.

The 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropyloxy)pyrimidineused as starting material may be obtained as follows:

4-[2-(2,2,2-Trifluoroethyl)guanidino]-2-methylsulphonylpyrimidine (0.15g.) was added to a mixture of 3-aminopropanol (0.075 g.), t-butanol (5ml.) and a 50% w/w dispersion of sodium hydride in mineral oil (0.05 g.)which was stirred under an argon atmosphere. The mixture was stirred atroom temperature for 2 hours, heated under reflux for 4 hours and thenevaporated to dryness. The residue was partitioned between 2N aqueousacetic acid and ether, and the aqueous phase basified with 17N NaOH andextracted three times with ether. The combined ether extracts were driedand evaporated to dryness to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropyloxy)pyrimidine(0.07 g.) which was used without further purification.

EXAMPLE 37

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylthio)pyrimidine(0.15 g), 1-methanesulphonyl-3-(2,2,2-trifluoroethyl)thiourea (0.12 g),ethanol (5 ml) and yellow mercuric oxide (0.22 g) was stirred at roomtemperature for 18 hours. The mixture was filtered, the filtrateevaporated to dryness and the residue was dissolved in acetonitrile.This solution was added to a solution of maleic acid in acetone and theprecipitate collected and recrystallised from ethanol to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-methanesulphonyl-3-[2,2,2-trifuloroethyl]guanidino)propylthio]pyrimidinehydrogen maleate (0.18 g.), m.p. 167°-168°.

The 1-methanesulphonyl-3-(2,2,2-trifluoroethyl)thiourea used as startingmaterial may be obtained as follows:

A solution of 2,2,2-trifluoroethylisothiocyanate (1.4 g.) in acetone (20ml.) was added to a solution of methanesulphonamide (0.95 g.) and sodiumhydroxide (0.44 g.) in water (10 ml.) and the mixture stirred and heatedunder reflux for 18 hours, and then evaporated to dryness. The residuewas dissolved in water and the solution washed with ethyl acetate andthen acidified with concentrated hydrochloric acid. The mixture wasextracted three times with ethyl acetate and the combined extracts driedand evaporated to dryness. The residue was triturated with acetonitrileand filtered and the filtrate evaporated to dryness. The residue wasdissolved in ether, and the solution extracted with aqueous sodiumbicarbonate solution. The extract was neutralised with N hydrochloricacid and the mixture extracted with ethyl acetate. The ethyl acetateextract was dried and evaporated to dryness to give1-methanesulphonyl-3-(2,2,2-trifluoroethyl)thiourea (0.45 g.) which wasused without further purification.

EXAMPLE 38

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(3-cyano-2-methylisothioureido)propylthio]pyrimidine(0.2 g.), methanol (2 ml.) and ethanolamine (0.5 ml.) was stirred atroom temperature for 3 days and then evaporated to dryness. Water wasadded to the residue, the mixture extracted with ethyl acetate and theethyl acetate extract dried and evaporated to dryness. The residue wasrecrystallised from acetonitrile to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-cyano-3-[2-hydroxyethyl]guanidino)propylthio]pyrimidine(0.1 g.), m.p. 114°-116°.

EXAMPLE 39

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(3-cyano-2-methylisothioureido)propylthio]pyrimidine(0.2 g.), N,N-diethylethylenediamine (0.5 ml.) and methanol (2 ml.) washeated under reflux for 24 hours and then evaporated to dryness. Waterwas added to the residue, the mixture extracted with ethyl acetate andthe ethyl acetate extract dried and evaporated to dryness. The residuewas purified by preparative thin layer chromatography using ethylacetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-cyano-3-[2-diethylaminoethyl]guanidino)propylthio]pyrimidine(0.08 g.), characterised as the bis hydrogen maleate, m.p. 76°-80° afterrecrystallisation from acetone.

EXAMPLE 40

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(3-cyano-2-methylisothioureido)propylthio]pyrimidine(0.34 g.) and ethylenediamine (0.5 g.) was stirred at room temperaturefor 4 hours and then evaporated to dryness. Water was added to theresidue, the mixture extracted with ethyl acetate, and the ethyl acetateextract dried and evaporated to dryness. A solution of the residue inacetone was added to a solution of maleic acid in acetone, and thecrystalline precipitate collected to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-cyano-3-[2-aminoethyl]guanidino)propylthio]pyrimidinebis hydrogen maleate, m.p. 173°-176°.

EXAMPLE 41

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-aminoethyl)thiomethylpyrimidine(0.31 g.), methanol (5 ml.) and 1,2-dimethoxycyclobutene-3,4-dione (0.14g.) was stirred at room temperature for 18 hours. A 33% w/v solution ofmethylamine in ethanol (5 ml.) was added and the mixture left at roomtemperature for 18 hours and then evaporated to dryness. The residue waspurified by preparative thin layer chromatography using ethylacetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give1-(2-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl-methylthio]ethylamino)-2-methylaminocyclobutene-3,4-dione (0.16 g.) characterised as the hydrogen maleate,m.p. 178°-184° after recrystallisation from a mixture of methanol andacetonitrile.

EXAMPLE 42

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-aminoethylthio)pyrimidine(0.25 g.), acetonitrile (5 ml.) and dimethyl(cyanoimido)dithiocarbonate(0.12 g.) was left at room temperature for 24 hours and then evaporatedto dryness. The residue was dissolved in a 33% w/v solution ofmethylamine in ethanol, and the solution left at room temperature for 24hours and then evaporated to dryness. The residue was recrystallisedfrom ethanol to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[2-(2-cyano-3-methylguanidino)ethylthio]pyrimidine,m.p. 218°-221°.

The 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-aminoethylthio)pyrimidineused as starting material may be obtained as follows:

A mixture of 2-thiocytosine (0.51 g.), dimethylformamide (5 ml.),N-(2-bromoethyl)phthalimide (1.12 g.) and1,8-diazabicyclo[5,4,0]undec-5-ene (0.67 g.) was stirred at roomtemperature for 6 hours and then evaporated to dryness. The residue wasstirred with a mixture of water and ethyl acetate and the insolublematerial collected to give 4-amino-2-(2-phthalimidoethylthio)pyrimidinewhich was used without further purification.

A mixture of 4-amino-2-(2-phthalimidoethylthio)pyrimidine (0.8 g.),2,2,2-trifluoroethylisothiocyanate (0.56 g.) and dimethyl formamide (2ml.) was stirred at 70° for 72 hours. The mixture was cooled, dilutedwith acetonitrile and filtered to give4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(2-phthalimidoethylthio)pyrimidine(0.7 g.), m.p. 238°-241°.

A mixture of4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(2-phthalimidoethylthio)pyrimidine(0.65 g.), dimethylformamide (10 ml.), ethanolic ammonia solution (5ml.) and yellow mercuric oxide was stirred at room temperature for 4hours. The mixture was filtered and the filtrate evaporated to drynessto give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-phthalimidoethylthio)pyrimidine(0.62 g.), m.p. 192°-195°.

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-phthalimidoethylthio)pyrimidine(0.6 g.) ethanol (20 ml.) and 99% hydrazine hydrate (0.5 ml.) was heatedunder reflux for 1 hour and then evaporated to dryness. The residue wasstirred with N hydrochloric acid and the mixture filtered. The filtratewas basified with 17N NaOH and the mixture extracted three times withether. The combined ether extracts were dried and then evaporated todryness to give4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-aminoethylthio)pyrimidine(0.25 g.) which was used without further purification.

EXAMPLE 43

A mixture of3-[2-(2,2,2-trifluoroethyl)guanidino]-1-(3-aminopropyl)pyrazole (0.13g.), dimethyl (methanesulphonylimido)dithiocarbonate (0.1 g.) andmethanol (2 ml.) was left at room temperature for 3 hours. A 33% w/vsolution of methylamine in ethanol (5 ml.) was added and the mixtureleft at room temperature for 18 hours and then evaporated to dryness. Asolution of the residue in ethyl acetate was added to a solution ofoxalic acid in ethyl acetate, and the precipitate collected andrecrystallised from ethanol to give3-[2-(2,2,2-trifluoroethyl)guanidino]-1-[3-(2-methanesulphonyl-3-methylguanidino)propyl]pyrazolehydrogen oxalate, m.p. 162°-163°.

The 3-[2-(2,2,2-trifluoroethyl)guanidino]-1-(3-aminopropyl)pyrazole usedas starting material may be obtained as follows:

2,2,2-Trifluoroethylisothiocyanate (3.4 g.) was added to a solution of3-amino-1-(2-cyanoethyl)pyrazole (2.72 g.) in acetonitrile (10 ml.) andthe solution left at room temperature for 18 hours. The mixture wasevaporated to dryness and the residue recrystallised from ethanol togive 3-[3-(2,2,2-trifluoroethyl)thioureido]-1-(2-cyanoethyl)pyrazole,m.p. 164°-165°.

A mixture of3-[3-(2,2,2-trifluoroethyl)thioureido]-1-(2-cyanoethyl)pyrazole (2.8g.), yellow mercuric oxide (4.0 g.), methanol (100 ml.) and saturatedethanolic ammonia solution (10 ml.) was stirred at room temperature for2 hours and then filtered. The filtrate was evaporated to dryness andthe residue partitioned between ether and water. The ether phase wasdried and evaporated to give3-[2-(2,2,2-trifluoroethyl)guanidino]-1-(2-cyanoethyl)pyrazolecharacterised as the hydrogen maleate, m.p. 141°-142° afterrecrystallisation from acetone.

A mixture of3-[2-(2,2,2-trifluoroethyl)guanidino]-1-(2-cyanoethyl)pyrazole (0.32g.), saturated ethanolic ammonia (10 ml.) and Raney nickel (0.2 g.) wasstirred vigorously under an atmosphere of hydrogen at room temperatureand atmospheric pressure for 3 hours. The mixture was filtered and thefiltrate evaporated to dryness to give 3-[2-(2,2,2-trifluoroethyl)guanidino]-1-(3-aminopropyl)pyrazole which wasused without further purification.

EXAMPLE 44

A mixture of4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylthio)pyrimidine(0.15 g.), 1,3-bis-(2,2,2-trifluoroethyl)thiourea (0.12 g.), yellowmercuric oxide (0.22 g.) and ethanol (20 ml.) was stirred at roomtemperature for 0.5 hours and then filtered and the filtrate evaporatedto dryness. A solution of the residue in acetone was added to a solutionof maleic acid in acetone and the crystalline precipitate collected togive4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2,3-bis[2,2,2-trifluoroethyl]guanidino)propylthio]pyrimidinebis hydrogen maleate (0.1 g.) m.p. 134°-136°.

The 1,3-di(2,2,2-trifluoroethyl)thiourea used as starting material maybe obtained as follows:

2,2,2-Trifluoroethylisothiocyanate (2.12 g.) was added to a mixture of2,2,2-trifluoroethylamine hydrochloride (1.36 g), triethylamine (1.01 g)and acetonitrile (10 ml.), and the mixture stirred at room temperaturefor 4 hours and then evaporated to dryness. The residue was partitionedbetween water and ethyl acetate, and the ethyl acetate phase was driedand evaporated to dryness. The residue was recrystallised from a mixtureof acetone and light petroleum ether (b.p. 60°-80°) to give1,3-di(2,2,2-trifluoroethyl)thiourea, m.p. 152°-153°.

EXAMPLE 45

To a stirred mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)-5-methylthiazoledihydrochloride (0.31 g.) and triethylamine (0.22 ml.) in ethanol (2ml.) was added dimethyl(methylsulphonylimido)dithiocarbonate (0.16 g.).The resulting colourless solution was stirred at ambient temperatureovernight and then evaporated to dryness to give a crude oil which waspurified by chromatography using CHCl₃ /methanol 9.75:0.25 v/v assolvent to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-methylsulphonyl-2-methylisothioureido)butyl]-5-methylthiazoleas an oil.

To the2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-methylsulphonyl-2-methylisothioureido)butyl]-5-methylthiazolewas added a 30% w/v ethanolic solution of methylamine (5 ml.) and themixture allowed to stand overnight at ambient temperature. It was thenevaporated to dryness and2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(2-methylsulphonyl-3-methylguanidino)butyl]-5-methylthiazole(0.17 g.) was isolated as the maleate salt from acetone, m.p. 165°-166°.

The2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)-5-methylthiazoleused as starting material may be prepared as follows:

A mixture of N-(6-chloro-5-oxoheptyl)phthalimide (0.7 g.),2,2,2-trifluoroethylamidinothiourea (0.48 g.) and ethanol (10 ml.) washeated under reflux for 15 minutes and allowed to cool to ambienttemperature. The resulting colourless solution was allowed to stand inan open vessel for 6 days, whereupon white cyrstalline rosettes of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-phthalimidobutyl)-5-methylthiazolehydrochloride (0.60 g.) precipitated.

To a mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-phthalimidobutyl)-5-methylthiazolehydrochloride (0.60 g.) in water (2 ml.) and ethanol (2 ml.) was addedsodium hydroxide pellets (0.2 g.). The resulting yellow solution washeated on a steam bath for 10 minutes and then allowed to cool toambient temperature. The reaction mixture was adjusted to pH3 byaddition of 2N hydrochloric acid and then reheated on a steam bath for 1hour. After cooling to ambient temperature the mixture was extractedthree times with equal volumes of ethyl acetate. The aqueous layer wasevaporated to dryness, azeotroped twice with toluene, the residuedissolved in methanol (10 ml.) and the solution filtered. The filtratewas evaporated to dryness to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)-5-methylthiazoledihydrochloride (0.31 g.) as an oil which was used without furtherpurification.

EXAMPLE 46

Trifluoroethylisothiocyanate (0.2 g.) in acetonitrile (6 ml.) was addedto a solution of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.5 g.)in acetonitrile (10 ml.), and the mixture was allowed to stand at roomtemperature for 2 hours. The residue obtained on evaporation of thesolvent was subjected to preparative thin layer chromatography usingchloroform/methanol/ammonia 85:15:0.5 v/v/v for development. Theappropriate zone of the chromatogram was isolated and extracted with hotethanol/chloroform 50:50 v/v (200 ml.). The residue was crystallisedfrom ethyl acetate/light petroleum ether (b.p. 60°-80°) to give2-[2-(2,2,2-trifluoroethyl)guanidion]-4-(4-[3-(2,2,2-trifluoroethyl)thioureido]butyl)thiazole.The n.m.r. spectrum in d₆ dimethylsulphoxide using tetramethylsilane asinteral standard (δ=0) included the following resonances (δ): 4.05 (2H,multiplet); 4.35 (2H, multiplet); 6.36 (1H, singlet).

EXAMPLE 47

A solution of silver nitrate (0.4 g.) in dimethylformamide (2 ml.) wasadded to a solution of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-[3-2,2,2-trifluoroethyl)thioureido]butyl)thiazole(0.3 g.) in dimethylformamide (4 ml.) and ammonia (s.g. 0.88, 4 ml.).After standing for 0.5 hours at room temperature the solution wastreated with excess gaseous hydrogen sulphide. Precipitated silversulphide was filtered off and the filtrate evaporated to dryness. Theresidue was treated with water (15 ml.), basified with aqueous sodiumhydroxide and extracted with ethyl acetate (2×30 ml.). Evaporation ofthe dried (magnesium sulphate) organic solution gave a red glass (0.25g.) which was dissolved in acetone (1 ml.) and the solution treated withan excess of maleic acid in acetone. Addition of a little ether inducedcrystallisation of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-[2-(2,2,2-trifluoroethyl)guanidiano]butyl)thiazoledihydrogen maleate. The n.m.r. spectrum in d₆ dimethylsulphoxide usingtetramethylsilane as internal standard (δ=0) included the followingresonances (δ): 4.05 (4H, multiplet); 6.1 (4H, singlet--maleic acid);6.36 (1H, singlet).

EXAMPLE 48

To a solution containing1-methanesulphonyl-3-(2,2,2-trifluoroethyl)thiourea (0.09 g.) and2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.13 g.)in dimethylformamide (4 ml.) was added a solution of silver nitrate(0.14 g.) in dimethylformamide (2 ml.). After allowing it to stand atroom temperature for 3 hours the reaction mixture was treated with anexcess of gaseous hydrogen sulphide and the precipitated silver sulphitefiltered off. The residue obtained on evaporation of the filtrate wassubjected to preparative thin layer chromatography usingchloroform/methanol/ammonia 90:10:0.1 v/v/v for development. Isolationof the appropriate zone of the chromatogram and extraction with hotethanol/chloroform 50:50 v/v (150 ml.) gave a yellow residue which oncrystallisation from methanol afforded2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[2-(2-methylsulphonyl)-3-[2,2,2-trifluoroethyl]guanidino)ethylthiomethyl]thiazolewhich contained one mole of methanol of crystallisation. The n.m.r.spectrum in d₆ dimethylsulphoxide containing a little d₄ acetic acid andusing tetramethylsilane as internal standard (δ=0) included thefollowing resonances (δ): 2.8 (3H, singlet); 4.0 (2H, multiplet); 4.1(2H, multiplet); 6.4 (1H, singlet).

EXAMPLE 49

A solution of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.3 g.)in acetonitrile/pyridine 1:1 v/v (5 ml.) was treated with aceticanhydride (0.1 g.) and the mixture allowed to stand at room temperaturefor 72 hours. The residue obtained on evaporation of the solvent wassubjected to preparative thin layer chromtography using ethylacetate/methanol/water 6:1:1 v/v/v for development. Isolation of theappropriate region of the chromatogram and extraction with hotethanol/chloroform 1:1 v/v (200 ml.) gave a residue which on treatmentwith ether/petroleum ether (b.p. 60°-80°) afforded2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-acetaminobutyl)thiazole. Then.m.r. spectrum in d₆ dimethylsulphoxide using tetramethylsilane asinternal standard (δ=0) included the following resonances (δ): 1.5 (4H,multiplet); 1.84 (3H, singlet); 3.1 (2H, multiplet); 4.1 (2H,multiplet); 6.4 (1H, singlet).

EXAMPLE 50

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.4 g.)and ethyl N-cyanoacetimidate (0.15 g.) in ethanol (3 ml.) was allowed tostand at room temperature for 6 hours. The residue obtained onevaporation of the solvent was subjected to preparative thin layerchromatography using ethyl acetate/methanol/water 12:2:1 v/v/v fordevelopment. Isolation of the appropriate zone of the chromatogram andextraction with hot ethanol/chloroform 1:1 v/v (200 ml.) gave aglass-like material which was dissolved in acetone (1.5 ml.) and treatedwith an excess of maleic acid in acetone. The crystalline precipitatewas collected and washed with a little acetone and ether to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-cyano-2-methylamidino)butyl]thiazolewhich contained 1.2 moles of maleic acid of crystallisation. The n.m.r.spectrum in d₆ dimethylsulphoxide using tetramethylsilane as internalstandard (δ=0) included the following resonances (δ): 1.6 (4H,multiplet); 2.22 (3H, singlet); 3.2 (2H, multiplet); 4.15 (2H,multiplet); 6.55 (1H, singlet).

EXAMPLE 51

To a solution of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(5-aminopentyl)thiazole (0.5 g.)in ethanol (8 ml.) was addeddimethyl(methylsulphonylimido)dithiocarbonate (0.35 g.). The mixture wasallowed to stand at room temperature for 2 days, evaporated to drynessand the residue purified by preparative thin layer chromatography usingmethanol/chloroform 1:9 v/v for development. The appropriate band wasextracted with ethanol/chloroform 1:1 v/v (200 ml.) and the solutionevaporated to dryness. The residue in ethanol (3 ml.) was treated withethanolic methylamine 33% (w/v, 30 ml.) and the mixture allowed to standovernight at room temperature. The solution was then evaporated todryness and the residue in acetone treated with excess maleic acid togive2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-methylsulphonyl-2-methylguanidino)pentyl]thiazoledihydrogen maleate. The n.m.r. spectrum in d₆ dimethylsulphoxide usingtetramethylsilane as internal standard (δ=0) included the followingresonances (δ): 1.5 (multiplet, 6H); 2.75 (doublet, 3H); 2.85 (singlet,3H); 3.1 (quartet, 2H); 4.2 (quartet, 2H); 6.7 (singlet, 1H).

The 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(5-aminopentyl)thiazole usedas starting material may be prepared in an analogous manner to thatdescribed for2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole inExample 6 but using N-(7-chloro-6-oxoheptyl)phthalimide as startingmaterial in place of N-(6-chloro-5-oxohexyl)phthalimide.

EXAMPLE 52

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(5-aminopentyl)thiazole (0.6 g.)and 2-nitroamino-6-methyl-4-pyrimidone (0.36 g.) in pyridine (4 ml.) washeated under reflux for 4 hours. After this period the pyridine wasremoved by evaporation and the residue heated at 160° for 20 minutes.The material was then cooled and purified by thin layer chromatographyusing ethyl acetate/methanol/water 12:2:1 v/v/v as developing solvent.The appropriate band was extracted with chloroform/ethanol 1:1 v/v (200ml.) and isolated by evaporation to dryness. The residue in acetone wasthen treated with excess maleic acid to precipitate6-methyl-2-(5-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]pentylamino)pyrimid-4-onedi(hydrogen maleate). The n.m.r. spectrum in d₆ dimethylsulphoxide usingtetramethylsilane as internal reference (δ=0) included the followingresonances (δ): 1.6 (multiplet, 6H); 2.15 (singlet, 3H); 3.3 (multiplet,2H); 4.2 (quartet 2 H); 5.55 (singlet, 1H); 6.7 (singlet, 1H).

EXAMPLE 53

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.7 g.)and 2-nitroamino-5-methyl-4(3H)-pyrimidone (0.3 g.) was heated underreflux in pyridine (3 ml.) for 3.5 hours. The mixture was thenevaporated to dryness and the residue purified by preparative thin layerchromatography using ethyl acetate/methanol/ 6:1:1 v/v/v fordevelopment. The appropriate band was extracted with chloroform/ethanol1:1 v/v (200 ml.). Evaporation of the solvent to dryness gave a red gumwhich was treated in acetone with excess maleic acid to give5-methyl-2-(4-[(-2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]butylamino)pyrimid-4-onecontaining 1.75 equivalents of maleic acid. The n.m.r. of this compoundin d₆ dimethylsulphoxide using tetramethylsilane as internal standard(δ=0) included the following resonances (δ): 1.6 (multiplet, 4H); 1.8(singlet, 3H); 3.3 (multiplet, 2H); 4.2 (quartet, 2H); 6.6 (singlet,1H); 7.5 (singlet, 1H).

EXAMPLE 54

To 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(5-aminopentyl)thiazole (0.4g.) in methanol (1.5 ml.) was added 1,2-dimethoxycyclobutene-3,4-dione(0.2 g.). After 2.5 hours at room temperature the mixture was evaporatedto dryness, and the residue purified by preparative thin layerchromatography using methanol/chloroform 1:9 v/v as development solvent.The appropriate band was isolated to give1-[5-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)pentylamino]-2-methoxycyclobutene-3,4-dione(0.22 g.) which was dissolved in propargylamine (1 g.) and the mixtureallowed to stand at room temperature overnight. The mixture was thenevaporated to dryness, and the residue purified by preparative thinlayer chromatography using chloroform/methanol/aqueous ammonia 90:10:1v/v/v as developing solvent. The product from this purification wastreated in methanol/acetone with excess maleic acid and the resultingsalt precipitated by the addition of diethyl ether to give1-[5-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)pentylamino]-2-propargylaminocyclobutene-3,4-dionehydrogen maleate. The n.m.r. spectrum in d₆ dimethylsulphoxide usingtetramethylsilane as internal standard (δ=0) included the followingresonances (δ): 1.5 (multiplet, 6H); 3.3 (singlet, 1H); 3.5 (multiplet,2H); 4.1 (quartet, 2H); 4.8 (quartet, 2H); 6.6 (singlet, 1H).

EXAMPLE 55

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(5-aminopentyl)thiazole (0.3 g.)and 1,2-dimethoxycyclobutene-3,4-dione (0.15 g.) in methanol (3 ml.) wasallowed to stand at room temperature for 4 hours. Ethanolic methylamine(33% w/v, 20 ml.) was then added and the solution allowed to standovernight. The mixture was evaporated to dryness and the residuepurified by preparative thin layer chromatography using ethylacetate/methanol/water 6:1:1 v/v/v as developing solvent to give1-[5-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)pentylamino]-2-methylaminocyclobutene-3,4-dioneas colourless gum (0.17 g.). The n.m.r. spectrum of the hydrogen maleatesalt in d₆ dimethylsulphoxide using tetramethylsilane as internalstandard (δ=0) included the following resonances (67 ): 1.5 (multiplet,6H); 2.6 (multiplet, 2H); 3.1 (doublet, 3H); 3.5 (multiplet, 2H); 4.1(multiplet, 2H); 6.55 (singlet, 1H).

EXAMPLE 56

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(5-aminopentyl)thiazole (1.0 g.)and 1-methylamino-1-methylthio-2-nitroethylene (0.55 g.) in acetonitrile(5 ml.) was heated under reflux for 4 hours. The mixture was thenevaporated to dryness and the residue purified by preparative thin layerchromatography using ethyl acetate/methanol/water 6:1:1 v/v/v asdeveloping solvent to give, on extraction of the appropriate band withchloroform/ethanol 1:1 v/v (200 ml.) and evaporation, a colourlessglass. This was treated with an excess of maleic acid in acetone and1-[5-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)pentylamino]-1-methylamino-2-nitroethylenewas precipitated as a salt containing 1.5 equivalent of maleic acid. Then.m.r. spectrum in d₆ dimethylsulphoxide using tetramethylsilane as aninternal standard (δ=0) included the following resonances (δ): 1.6(multiplet, 6H); 2.8 (broad doublet, 3H); 3.2 (multiplet, 2H); 4.2(quartet, 2H); 6.5 (singlet, 1H); 6.6 (singlet, 1H).

EXAMPLE 57

To2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-methylisothioureido)pentyl]thiazole(0.25 g.) in ethanol (1 ml.) was added ethanolic methylamine (33% w/v,30 ml.). The mixture was allowed to stand overnight at room temperatureand then evaporated to dryness to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-methylguanidino)pentyl]thiazole.The n.m.r. spectrum in d₆ dimethylsulphoxide containingtetramethylsilane as internal standard (δ=0) included the followingresonances (δ): 1.5 (multiplet, 6H); 2.7 (doublet, 3H); 3.1 (multiplet,2H); 4.1 (multiplet, 2H); 6.4 (singlet, 1H).

The2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-methylisothioureido)pentyl]thiazoleused as starting material may be prepared as follows:

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(5-aminopentyl)thiazole (1.4 g.)and dimethyl (cyanoimido)dithiocarbonate (0.9 g.) in ethanol (10 ml.)was allowed to stand at room temperature for 6 days. The solvent wasthen evaporated and the residue purified by column chromatogrpahy onsilica gel using methanol/chloroform 1.19 v/v as solvent. The resulting2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-methylisothioureido)pentyl]thiazolewas used without further purification.

EXAMPLE 58

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-methylisothioureido)pentyl]-thiazole(0.5 g.) and 1,2-diaminoethane (1.5 ml.) in ethanol (1 ml.) was allowedto stand at room temperature overnight. The mixture was then evaporatedto dryness and the residue purified by preparative medium pressureliquid chromatography on silica gel using methanol/chloroform 1:4 v/v assolvent to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-[2-aminoethyl]guanidino)pentyl]thiazoleas a straw coloured gum. A sample of the salt prepared with maleic acidincluded the following n.m.r. resonances when examined in d₆dimethylsulphoxide containing tetramethylsilane as an internal standard(δ=0) (δ): 1.5 (multiplet, 6H); 3.0 (multiplet, 4H); 3.3 (multiplet,2H); 4.1 (multiplet, 2H); 6.5 (singlet, 1H).

EXAMPLE 59

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(5-aminopentyl)thiazole (0.3 g.)and ethyl N-cyanopropionimidate (0.13 g.) in ethanol (3 ml.) was allowedto stand at room temperature for 6 hours then evaporated to dryness andthe residue purified by preparative thin layer chromatography usingethyl acetate/methanol/water 12:2:1 v/v/v as developing solvent. Thepurified product was treated in acetone with excess maleic acid inacetone to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-ethylamidino)pentyl]thiazolecontaining 1.2 equivalents of maleic acid. The n.m.r. spectrum in d₆dimethylsulphoxide containing tetramethylsilane as an internal standard(δ=0) included the following resonances (δ): 1.2 (triplet, 3H); 1.5(multiplet, 6H); 2.5 (multiplet, 4H); 3.2 (quartet, 2H); 4.2 (quartet,2H); 6.55 (singlet, 1H).

EXAMPLE 60

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.75 g.)and 1,1-di(methylthio)-2-nitroethylene (0.43 g.) was allowed to stand inacetonitrile (12 ml.) at room temperature overnight. The resultingmixture was purified by preparative thin layer chromatography usingchloroform/methanol 9:1 v/v as developing solvent. The product wasisolated as a minor band and extracted with chloroform/ethanol 1:1 v/v(200 ml.). On evaporation to dryness and treatment with maleic acid inmethanol/acetone/ether there was obtained1,1-di[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]-2-nitroethylenecontaining 1.75 equivalents of maleic acid, m.p. 123°-125° (decomp).

EXAMPLE 61

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.12 g.)and2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-isothiocyanatobutyl]thiazole(0.12 g.) in methanol (3 ml.) was allowed to stand at room temperatureovernight. The mixture was then evaporated to dryness and purified bypreparative thin layer chromatography using methanol/chloroform/ammonia85:15:1 v/v/v as developing solvent. The appropriate band was extractedwith chloroform/ethanol 1:1 v/v (200 ml.) and the resulting solutionevaporated to give a brown gum. This was treated in acetone with excessmaleic acid to give1,3-di[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]thioureacontaining 2.25 equivalents of maleic acid. The n.m.r. spectrum in d₆dimethylsulphoxide containing tetramethylsilane as internal standard(δ=0) included the following resonances (δ): 1.5 (multiplet, 8H); 3.3(multiplet, 4H); 4.1 (quartet, 4H); 6.5 (singlet, 2H).

The2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-isothiocyanatobutyl]thiazoleused as starting material may be prepared as follows:

A solution of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.75 g.)in tetrahydrofuran (20 ml.) was added dropwise over 15 minutes to astirred solution of thiocarbonyldiimidazole (0.5 g.) in tetrahydrofuran(20 ml.). The mixture was then stirred at room temperature for 20minutes and then evaporated to dryness. The residue was partitionedbetween ethyl acetate (50 ml.) and water (20 ml.). The organic layer waswashed with water (2×20 ml.) and then evaporated to dryness. The residuewas purified by preparative thin layer chromatography usingmethanol/chloroform 1:9 v/v as developing solvent. The purified productwas isolated as colourless gum and used without further purification.

EXAMPLE 62

A mixture of 2-(2-guanidino)-4-(4-aminobutyl)thiazole (0.30 g.) and2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-isothiocyanatobutyl)thiazole(0.35 g.) in tetrahydrofuran (30 ml.) was allowed to stand at roomtemperature overnight. The solution was then evaporated to dryness, andthe residue purified by preparative thin layer chromatography usingmethanol/chloroform 15:85 v/v as developing solvent. The appropriateband was extracted with chloroform/ethanol (1:1 v/v, 200 ml.) and thisextract was evaporated to give a fawn glass. This was treated in acetonewith excess maleic acid to give1-[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butyl]-3-[4-(2-guanidinothiazol-4-yl)butyl]thioureacontaining 2.25 equivalents of maleic acid. The n.m.r. spectrum in d₆dimethylsulphoxide containing tetramethylsilane as internal standard(δ=0) included the following resonances (δ): 1.5 (multiplet, 8H); 3.35(multiplet, 4H); 4.1 (quartet, 4H); 6.45 (singlet, 1H); 6.85 (singlet,1H).

EXAMPLE 63

A mixture of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazoledihydrochloride (0.5 g.), triethylamine (1 ml.) and2-[2-(2,2,2-trifluoroethyl)guanidino]-(4-isothiocyanatobutyl)thiazole(0.5 g.) in tetrahydrofuran (15 ml.) was allowed to stand at roomtemperature overnight. The solution then was filtered, and the filtrateevaporated to dryness. The residue was purified by preparative thinlayer chromatography using ethyl acetate/methanol/ammonia 6:1:1 v/v/v asdeveloping solvent. The appropriate band was isolated and furtherpurified by preparative thin layer chromatography usingmethanol/chloroform/ammonia 15:85:1 v/v/v as developing solvent. Theappropriate band after extraction and evaporation yielded a brown gum.This was treated in acetone with excess maleic acid to give1-[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butyl]-3-[2-([4-methylimidazol-5-yl]methylthio)ethyl]thioureacontaining 2.25 equivalents of maleic acid. The n.m.r. spectrum in d₆dimethyl sulphoxide containing tetramethylsilane as internal standard(δ=0) included the following resonances (δ): 1.5 (multiplet, 4H); 2.25(singlet, 3H); 2.5 (multiplet, 4H); 3.3 (multiplet, 4H); 3.8 (singlet,2H); 4.1 (quartet, 2H); 6.45 (singlet, 1H); 8.8 (singlet, 1H).

EXAMPLE 64

A mixture of2-[2-(2,2,2-trifluoromethyl)guanidino]-4-(4-aminobutyl)thiazole (0.45g.) and 2-chloropyrimidine (0.18 g.) was heated under reflux inacetonitrile (5 ml.) for 16 hours. The reaction mixture was thenevaporated to dryness and the residue purified by medium pressure liquidchromatography on silica gel using chloroform/methanol/ammonia1900:100:5 v/v/v as eluant. The appropriate fraction was evaporated todryness and the residue recrystallized from acetonitrile to give2-(4-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]butylamino)pyrimidine(0.29 g.), m.p. 173°-175°.

EXAMPLE 65

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-[2-aminophenyl]thioureido)butyl]thiazole(0.45 g.), silver nitrate (0.34 g.) and triethylamine (0.28 ml.) indimethylformamide (3 ml.) was stirred vigorously at ambient temperatureovernight. Hydrogen sulphide gas was then bubbled through the reactionmixture until no more solid precipitated. The reaction mixture wasfiltered through a pad of diatomaceous earth and the filtrate evaporatedto dryness in vacuo. The residue was purified by low pressure liquidchromatography using chloroform/methanol/ammonia, 9:1:0.1 v/v/v aseluant to give2-[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]benzimidazolewhich was converted to the hydrogen maleate salt (0.25 g.), m.p.183°-186°.

The2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-[2-aminophenyl]thioureido)butyl]thiazoleused as starting material may be obtained as follows:

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-isothiocyanatobutyl)thiazole(0.33 g.) and o-phenylenediamine in alcohol (5 ml.) was heated underreflux for 2 hours. Evaporation of the reaction mixture to dryness gave2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-[2-aminophenyl]thioureido)butyl]thiazoleas an oil which was used without further purification.

EXAMPLE 66

1-Methylamino-1-methylthio-2-nitroethylene (0.16 g.) was added to asolution of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.33 g.) in acetonitrile (10 ml.) and the mixture heated under refluxfor 30 hours. The mixture was evaporated to dryness and the residual gumwas purified by column chromatography on Merck Kieselgel 60 usingacetonitrile followed by chloroform/methanol/ammonia 8:2:0.2 v/v/v aseluting solvents. Fractions containing the product were evaporated andthe residual gum was further purified by preparative thin layerchromatography using chloroform/methanol/ammonia 8:2:0.2 v/v/v asdeveloping solvent.

The1-[2-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-ylmethylthio)ethylamino]-1-methylamino-2-nitroethylene(0.06 g.) obtained was characterised as the hydrogen maleate, m.p.144°-147° (decomp.).

EXAMPLE 67

Dimethyl (methylsulphonylimido)dithiocarbonate (0.13 g.) was added to asolution of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.2 g.) in ethanol (10 ml.) and stirred at room temperature for 16hours. The solvent was removed by evaporation and the residual gum waspurified by preparative thin layer chromatography usingchloroform/methanol/ammonia 8:2:0.2 v/v/v as developing solvent. Theappropriate zone of the chromatogram was isolated and extracted withmethanol/ammonia 10:1 v/v (50 ml.). The solvent was evaporated and theresidue was dissolved in acetonitrile (10 ml.) filtered and evaporated.The residual gum was dissolved in methanol (3 ml.) and treated with asolution of fumaric acid (0.1 g.) in methanol (5 ml.). The solution wasevaporated and the residue was triturated with ethyl acetate to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[2-(3-methylsulphonyl-2-methylisothioureido)ethylthiomethyl]thiazoletrifumarate, m.p. 148° (decomp.).

EXAMPLE 68

2-[2-(2,2,2-Trifluoroethyl)guanidino]-4-[2-(3-methylsulphonyl-2-methylisothioureido)ethylthiomethyl]thiazole(0.4 g.) was dissolved in ethanolic methylamine (33% w/v 15 ml.) andallowed to stand at room temperature for 64 hours. The solvent wasevaporated and the residual gum was purified by preparative thin layerchromatography using chloroform/methanol/ammonia 8:2:0.2 v/v/v asdeveloping solvent. The appropriate zone of the chromatogram wasisolated and extracted with methanol/ammonia 10:1 v/v (50 ml.). Thesolvent was evaporated and the residual gum was dissolved inacetonitrile, filtered and the filtrate evaporated. The residual gum wasdissolved in methanol and treated with a solution of excess fumaric acidin methanol. The solvent was evaporated and the residue triturated withacetonitrile to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[2-(2-methylsulphonyl-3-methylguanidino)ethylthiomethyl]thiazoleas a cream solid (0.29 g.), m.p. 118°-123° (decomp.), containing 1.5molar equivalents of fumaric acid.

EXAMPLE 69

Dimethyl (methylsulphonylimido)dithiocarbonate (0.2 g.) and2-[2-(2,2,3,3,3-pentafluoropropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.36 g.) were dissolved in ethanol (5 ml.) and allowed to stand at roomtemperature for 2 hours. The mixture was evaporated to dryness and theresidual gum was dissolved in ethanolic methylamine (33% w/v, 3 ml.) andallowed to stand at room temperature for 2 hours. The mixture wasevaporated to dryness and the residual gum was purified by preparativethin layer chromatography using ethyl acetate/methanol/ammonia 6:1:1v/v/v as developing solvent. The appropriate zone of the chromatogramwas isolated and extracted with methanol/ammonia 10:1 v/v (50 ml.). Thesolvent was evaporated and the residue was dissolved in ethyl acetate(10 ml.), filtered and the filtrate was treated with a solution ofmaleic acid (0.05 g.) in ethyl acetate (10 ml.). The resultingprecipitate was filtered to give2-[2-(2,2,3,3,3-pentafluoropropyl)guanidino]-4-[2-(2-methylsulphonylmethylguanidino)ethylthiomethyl]thiazoleas a cream solid (0.06 g.), m.p. 149°-151° containing maleic acid (1.25molar equivalent) and water (1 molar equivalent).

The2-[2-(2,2,3,3,3-pentafluoropropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleused as starting material may be prepared as follows:

A mixture of 2,2,3,3,3-pentafluoropropylamine hydrochloride (5.0 g.) andsodium dicyanamide (2.4 g.) in butanol (100 ml.) was heated under refluxfor 6 hours. The suspension was cooled, filtered and evaporated todryness. The residual gum and thioacetamide (2.25 g.) were suspended inwater (50 ml.) and cooled to 5°. Concentrated hydrochloric acid (3 ml.)was added dropwise whilst the suspension was stirred and the resultingmixture was heated at 100° for 1 hour. The mixture was filtered and thefiltrate basified with saturated aqueous potassium carbonate solutionand extracted with ethyl acetate (2×100 ml.). The ethyl acetate layerwas dried (sodium sulphate) and evaporated to dryness. A solution ofmaleic acid (3.1 g.) in acetone (10 ml.) was added to the residual gumand the resulting solid was filtered and added to 1N sodium hydroxidesolution. The mixture was extracted with ethyl acetate (100 ml.) whichwas then dried (sodium sulphate) and evaporated to dryness. The residualgum and 1,3-dichloroacetone (1.5 g.) were dissolved in acetone (50 ml.),treated with concentrated hydrochloric acid (0.1 ml.) and stirred atroom temperature for 40 hours. The mixture was evaporated to dryness andthe residual gum triturated with ether and the resulting solid (1.6 g.)was filtered. The solid and 2-aminoethanethiol hydrochloride (1 g.) weredissolved in ethanol (30 ml.), mixed with a solution of sodium hydroxide(1 g.) in water (15 ml.) and stirred at room temperature for 16 hours.The mixture was evaporated to dryness and the residual gum waspartitioned between ethyl acetate (100 ml.) and water (100 ml.). Theethyl acetate layer was washed with water (50 ml.), dried (magnesiumsulphate) and evaporated to dryness to give2-[2-(2,2,3,3,3-pentafluoropropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleas a gum (1.5 g.) which was used without further purification.

EXAMPLE 70

Dimethyl (methylsulphonylimido)dithiocarbonate (0.055 g.) and2-[2-(2,2,2-trichloroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.11 g.) were dissolved in ethanol (2 ml.) and allowed to stand at roomtemperature for 16 hours. The mixture was evaporated to dryness and theresidual gum was dissolved in ethanolic methylamine (33% w/v 5 ml.) andallowed to stand at room temperature for 5 hours. The mixture wasevaporated to dryness and the residual gum was purified by preparativethin layer chromatography using ethyl acetate/methanol/ammonia 6:1:1v/v/v as developing solvent. The appropriate zone of the chromatogramwas isolated and extracted with methanol/ammonia 10:1 v/v (50 ml.). Thesolvent was evaporated and the residue was dissolved in ethyl acetate,filtered, and added to a solution of maleic acid (0.05 g.) in ethylacetate. The resulting solid was filtered to give2-[2-(2,2,2-trichloroethyl)guanidino]-4-[2-(2-methylsulphonyl-3-methylguanidino)ethylthiomethyl]thiazoleas a pale brown solid (0.06 g.), m.p. 126°-130° (decomp.) containing1.25 molar equivalents of maleic acid.

The2-[2-(2,2,2-trichloroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleused as starting material may be prepared as follows:

A mixture of 2,2,2-trichloroethylamine hydrochloride (4 g.) and sodiumdicyanamide (1.95 g.) in butanol (100 ml.) was heated under reflux for 6hours. The suspension was cooled, filtered and the filtrate evaporatedto dryness. The residual gum and thioacetamide (1.8 g.) were mixed withwater (100 ml.) and cooled to 5°. Concentrated hydrochloric acid (2.2ml.) was added dropwise whilst the suspension was stirred and theresulting mixture was then heated at 100° for 1 hour. The solution wasfiltered and the filtrate was basified with 10N sodium hydroxidesolution and extracted with ethyl acetate (2×100 ml.). The organic layerwas dried (sodium sulphate) and evaporated. The residual gum wasdissolved in acetone (10 ml.) and added to a solution of maleic acid(2.55 g.) in acetone (20 ml.). The precipitated solid was filtered,added to 1N sodium hydroxide solution and the product was extracted withethyl acetate (100 ml.). The ethyl acetate was dried (magnesiumsulphate) and the solvent evaporated.

The residual gum and 1,3-dichloroacetone (1.41 g.) were dissolved inacetone (20 ml.), treated with concentrated hydrochloric acid (0.01 ml.)and stirred at room temperature for 40 hours. The suspension wasfiltered and the cream solid was dissolved in ethanol (30 ml.).2-Aminoethanethiol (0.5 g.) was added to the solution and this mixturewas added to a solution of sodium hydroxide (0.45 g.) in water (15 ml.)and stirred at room temperature for 16 hours. The solvent was evaporatedand the residual gum was partitioned between ethyl acetate (100 ml.) andwater (100 ml.). The ethyl acetate layer was washed with water (50 ml.),dried (magnesium sulphate) and evaporated to give2-[2-(2,2,2-trichloroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleas a gum (0.11 g.) which was used without further purification.

EXAMPLE 71

The process described in Example 70 was repeated using2-[2-(2-chloro-2,2-difluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.33 g.) in place of2-[2-(2,2,2-trichloroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleand there was thus obtained2-[2-(2-chloro-2,2-difluoroethyl)guanidino]-4-[2-(2-methylsulphonyl-3-methylguanidino)ethylthiomethyl]thiazoleas a cream solid (0.27 g.), m.p. 130°-133° (decomp.), containing 1.2molar equivalents of maleic acid.

The2-[2-(2-chloro-2,2-difluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleused as starting material may be obtained as follows:

Lithium aluminium hydride (4.5 g.) was added to ether (150 ml.) stirredunder an atmosphere of argon. The suspension was cooled to 5° and asolution of chlorodifluoroacetamide (13.1 g.) in ether (50 ml.) wasadded dropwise. The mixture was stirred at room temperature for 2 hoursthen a saturated aqueous solution of sodium chloride (15 ml.) was addeddropwise. The reaction mixture was filtered and the solid residue waswashed with ether (2×100 ml.). The ether solutions were combined, dried(magnesium sulphate) and treated with an excess of a saturated solutionof hydrogen chloride in ether. The precipitate was filtered to give2-chloro-2,2-difluoroethylamine hydrochloride (6.0 g.), m.p. 224°-226°(with sublimation).

2-Chloro-2,2-difluoroethylamine hydrochloride (4 g.) and sodiumdicyanamide (2.5 g.) were suspended in butanol (20 ml.) and heated underreflux for 6 hours. The suspension was cooled, filtered and evaporatedto dryness. The residual gum and thioacetamide (2.5 g.) were suspendedin water (30 ml.) and cooled to 5°. Concentrated hydrochloride acid (3ml.) was added dropwise and the mixture was heated at 100° for 30minutes. The mixture was cooled and extracted with ethyl acetate (50ml.). The ethyl acetate layer was extracted with 1N hydrochloric acidand the aqueous extracts were combined, basified with 10N sodiumhydroxide solution and extracted with ethyl acetate (100 ml.). The ethylacetate layer was dried (magnesium sulphate) and to this solution wasadded a solution of maleic acid (2.5 g.) in ethyl acetate (50 ml.). Theresulting precipitate was filtered and added to 1N sodium hydroxidesolution. The mixture was extracted with ethyl acetate (100 ml.) whichwas then dried (magnesium sulphate) and evaporated to dryness. Theresidual gum and 1,3-dichloroacetone (1.35 g.) were dissolved in acetone(15 ml.) and stirred at room temperature for 40 hours. The mixture wasevaporated and triturated with ether to give a crystalline precipitate.The solid was filtered and dissolved in ethanol (50 ml.).2-Aminoethanethiol (1.7 g.) was added to the solution followed by asolution of sodium hydroxide (1.5 g.) in water (25 ml.) and the mixturewas stirred at room temperature for 1 hour. The mixture was evaporatedto dryness and the residue partitioned between ethyl acetate (100 ml.)and water (100 ml.). The ethyl acetate layer was dried (magnesiumsulphate) and evaporated to dryness to give2-[2-(2-chloro-2,2-difluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleas a gum (2.8 g.) which was used without further purification.

EXAMPLE 72

Dimethyl (methylsulphonylimido)dithiocarbonate (0.11 g.) was added to asolution of2-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.2 g.) in ethanol (3 ml.) and the mixture allowed to stand at roomtemperature for 64 hours. The solvent was removed by evaporation and theresidue was dissolved in ethanolic methylamine (33% w/v, 10 ml.) andallowed to stand at room temperature for 2 hours. After evaporation ofsolvent the residual gum was purified by column chromatography usingchloroform/methanol/ammonia 9:1:0.1 v/v/v as eluting solvent. Fractionscontaining the product were evaporated and the residue was furtherpurified by preparative thin layer chromatography using ethylacetate/methanol/ammonia 6:1:1 v/v/v as developing solvent. Theappropriate zone of the chromatogram was isolated and extracted withmethanol/ammonia 10:1 v/v (50 ml.). The solvent was evaporated and theresidual gum was dissolved in ethyl acetate, filtered and the filtratewas treated with a solution of maleic acid (0.05 g.) in ethyl acetate togive 2-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-4-[2-(2-methylsulphonyl-3-methylguanidino)ethylthiomethyl]thiazolehydrogen maleate (0.07 g.), m.p. 144°-147° (decomp.).

The2-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleused as starting material may be prepared as follows:

A mixture of 2,2,3,3-tetrafluoropropylamine hydrochloride (5 g.) andsodium dicyanamide (2.8 g.) in butanol (25 ml.) was heated under refluxfor 6 hours. The suspension was cooled, filtered and evaporated todryness. The residual gum and thioacetamide (2.8 g.) were suspended inwater (50 ml.) and cooled to 5°. Concentrated hydrochloric acid (3 ml.)was added dropwise whilst the suspension was stirred and the resultingmixture was heated at 100° C. for 30 minutes. The mixture was extractedwith ethyl acetate (50 ml.) and the organic layer was re-extracted with1N hydrochloric acid (25 ml.). The aqueous layers were combined,basified with 10N sodium hydroxide solution and the product wasextracted with ethyl acetate (100 ml.). The ethyl acetate layer wasdried (magnesium sulphate) and mixed with a solution of maleic acid (2.5g.) in ethyl acetate. The resulting precipitate was filtered and addedto 1N sodium hydroxide solution (50 ml.) and extracted with ethylacetate (50 ml.). The ethyl acetate layer was dried (magnesium sulphate)and evaporated to dryness. The residual gum and 1,3-dichloroacetone (2.2g.) were dissolved in acetone (50 ml.), treated with concentratedhydrochloric acid (0.1 ml.) and stirred at room temperature for 21hours. The mixture was evaporated to dryness. The residual gum and2-aminoethanethiol hydrochloride (3 g.) were dissolved in ethanol (60ml.) and to this solution was added a solution of sodium hydroxide (3g.) in water (30 ml.). The mixture was stirred at room temperature for16 hours and evaporated to dryness. The residual gum was partitionedbetween ethyl acetate (100 ml.) and water (100 ml.). The ethyl acetatelayer was washed with water (50 ml.), dried (magnesium sulphate) andevaporated to dryness. The residual gum was purified by columnchromatography using chloroform/methanol/ammonia 9:1:0.1 v/v/v aseluting solvent to give2-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleas a gum (1.05 g.) which was used without further purification.

EXAMPLE 73

Dimethyl (methylsuphonylimido)dithiocarbonate (0.1 g.) and2-[2-(2,2-difluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.15 g.) were dissolved in ethanol (3 ml) and heated under reflux for20 minutes. The mixture was evaporated to dryness and the residual gumwas dissolved in ethanolic methylamine (33% w/v, 3 ml.) and allowed tostand at room temperature for 16 hours. The mixture was evaporated todryness and the residual gum was purified by preparative thin layerchromatography using ethyl acetate/methanol/ammonia 6:6:1 v/v/v asdeveloping solvent. The appropriate zone of the chromatogram wasisolated and extracted with methanol/ammonia 10:1 v/v (50 ml.). Thesolvent was evaporated and the residue was dissolved in ethyl acetate,filtered and added to a solution of maleic acid (0.1 g.) in ethylacetate. The resulting solid was filtered to give2-[2-(2,2-difluoroethyl)guanidino]-4-[2-(2-methylsulphonyl-3-methylguanidino)ethylthiomethyl]thiazoleas a cream solid (0.07 g.), m.p. 85°-89°, containing 1.4 molarequivalents of maleic acid.

The2[2-(2,2-difluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleused as starting material may be prepared as follows:

A mixture of 2,2-difluoroethylamine hydrochloride (5 g.) and sodiumdicyanamide (3.8 g.) in butanol (60 ml.) was heated under reflux for 6hours. The suspension was cooled, filtered and the filtrate evaporatedto dryness. The residual gum and thioacetamide (3.8 g.) were mixed withwater (50 ml.) and cooled to 5°. Concentrated hydrochloric acid (4 ml.)was added dropwise whilst the suspension was stirred and the mixture wasthen heated at 100° for 30 minutes. The reaction mixture was extractedwith ethyl acetate (50 ml.) and the ethyl acetate was re-extracted with1N hydrochloric acid (50 ml.). The combined aqueous extracts werebasified with 10N sodium hydroxide solution and extracted with ethylacetate (100 ml.). The organic layer was dried (magnesium sulphate) andadded to a solution of maleic acid (6 g.) in ethyl acetate (50 ml.).Petroleum ether (b.p. 60°-80°) was added and the salt crystallised. Thesolid was filtered, added to 1N sodium hydroxide solution and extractedwith ethyl acetate (100 ml.). The ethyl acetate layer was dried(magnesium sulphate) and evaporated to dryness. The residual gum and1,3-dichloroacetone (1.5 g.) were dissolved in acetone (20 ml.) andstirred at room temperature for 21 hours. The solvent was evaporated andthe residue triturated with ether and filtered to give a solid (1.6 g.).This solid and 2-aminoethanethiol (1.7 g.) were dissolved in ethanol (25ml.) and added to a solution of sodium hydroxide (1.6 g.) in water (12ml.). The mixture was stirred at room temperature for 2 hours and thesolvent was removed by evaporation. The residue was partitioned betweenethyl acetate (100 ml.) and water (100 ml.) and the ethyl acetate layerwas dried (magnesium sulphate) and evaporated to dryness to give2-[2-(2,2-difluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleas a gum (1.5 g.) which was used without further purification.

EXAMPLE 74

Dimethyl (methylsulphonylimido)dithiocarbonate (0.24 g.) and2-[2-(1,1,1-trifluoroisopropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.4 g.) were dissolved in ethanol (5 ml.) and heated under reflux for30 minutes. The solvent was evaporated and the residual gum wasdissolved in ethanolic methylamine (33% w/v, 3 ml.) and allowed to standat room temperature for 16 hours. The solvent was evaporated and theresidual gum was purified by preparative thin layer chromatography usingethyl acetate as developing solvent. The appropriate zone of thechromatogram was isolated and extracted with methanol/ammonia 10:1 v/v(50 ml.). The solvent was evaporated and the residual gum was againsubjected to preparative thin layer chromatography using the conditionsdescribed above. The isolated gum was dissolved in ethyl acetate andadded to a solution of maleic acid (0.014 g.) in ethyl acetate. Thesolvent was evaporated to give2-[2-(1,1,1-trifluoroisopropyl)guanidino]-4-[2-(2-methylsulphonyl-3-methylguanidino)ethylthiomethyl]thiazolehydrogen maleate as a straw-coloured gum. The n.m.r. spectrum in d₄methanol using tetramethylsilane as internal standard (δ=0) included thefollowing resonances (δ): 1.5 (3H, doublet); 2.8 (3H, singlet); 2.9 (3H,singlet); 3.8 (2H, singlet); 4.6 (1H, complex); 7.1 (1H, singlet).

The2-[2-(1,1,1-trifluoroisopropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleused as starting material may be obtained as follows:

1,1,1-Trifluoroisopropylamine hydrochloride (2 g.) and sodiumdicyanamide (1.2 g.) in butanol (20 ml.) were heated under reflux for 6hours. The suspension was cooled, filtered and the filtrate evaporatedto dryness. The residual gum and thioacetamide (1.2 g.) were mixed withwater (20 ml.) and cooled to 5°. Concentrated hydrochloric acid (2 ml.)was added dropwise whilst the suspension was stirred and the resultingmixture was heated at 100° for 30 minutes. The reaction mixture wasextracted with ethyl acetate (50 ml.) and the organic layer wasre-extracted with 1N hydrochloric acid. The aqueous extracts werecombined, basified with 10N sodium hydroxide solution and extracted withethyl acetate (100 ml.). The organic layer was dried (magnesiumsulphate) and evaporated to dryness,. The residual gum and1,3-dichloroacetone (0.6 g.) were dissolved in acetone (10 ml.) andallowed to stand at room temperature for 88 hours. The solvent wasevaporated to dryness and dissolved in ethanol (20 ml.).2-Aminoethanethiol (0.6 g.) was added and this mixture was then added toa solution of sodium hydroxide (0.5 g.) in water (10 ml.). Afterstirring for 2 hours at room temperature, the mixture was evaporated todryness and the residual gum wa partitioned between ethyl acetate (50ml.) and water (50 ml.). The organic layer was dried (magnesiumsulphate) and evaporated to dryness to give2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleas a gum (0.4 g.) which was used without further purification.

EXAMPLE 75

Dimethyl (cyanoimido)dithiocarbonate (0.05 g.) and2-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.12 g.) were dissolved in ethanol (2 ml.) and allowed to stand at roomtemperature for 16 hours. The mixture was evaporated to dryness,dissolved in ethanolic methylamine (33% w/v, 5 ml.) and allowed to standat room temperature for 16 hours. The mixture was evaporated to drynessand the residue was purified by preparative thin layer chromatographyusing ethyl acetate/methanol/ammonia 6:1:1 v/v/v as developing solvent.The appropriate zone of the chromatogram was isolated and extracted withmethanol/ammonia 50:1 v/v. The solvent was evaporated and the residualgum was dissolved in ethyl acetate, filtered and added to a solution ofmaleic acid (0.05 g.) in ethyl acetate. The precipitated solid wasfiltered to give2-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazolehydrogen maleate (0.1 g.), m.p. 146°-8° (decomp.).

EXAMPLE 76

The process described in Example 75 was repeated using2-[2-(2-chloro-2,2-difluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole0.33 g. in place of2-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-4[(2-aminoethyl)thiomethyl]thiazoleand there was thus obtained2-[2-(2-chloro-2,2-difluoroethyl)guanidino]-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole(0.35 g.), m.p. 118°-122° (decomp.) containing 1.25 molar equivalents ofmaleic acid.

EXAMPLE 77

Dimethyl (cyanoimido)dithiocarbonate (0.07 g.) and2-[2-(2,2-difluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.15 g.) were dissolved in ethanol (3 ml.) and heated under reflux for20 minutes. The solvent was evaporated and the residual gum wasdissolved in ethanolic methylamine (33% w/v, 3 ml.) and allowed to standat room temperature for 16 hours. The solvent was evaporated and theresidual gum purified by preparative thin layer chromatography usingethyl acetate/methanol/ammonia 6:1:1 v/v/v as developing solvent. Theappropriate zone of the chromatogram was isolated and extracted withmethanol/ammonia 10:1 v/v. The solvent was evaporated and the residuewas dissolved in ethyl acetate, filtered and added to a solution ofmaleic acid (0.1 g.) in ethyl acetate. The precipitate was filtered togive2-[2-(2,2-difluoroethyl)guanidino]-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole(0.11 g.), m.p. 108°-112° (decomp.) containing 1.25 molar equivalents ofmaleic acid.

EXAMPLE 78

1-Methylamino-1-methylthio-2-nitroethylene (0.05 g.) and2-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.12 g.) were dissolved in acetonitrile (5 ml.) and heated under refluxfor 16 hours. The solvent was evaporated and the residual gum waspartitioned between ethyl acetate (25 ml.) and 1N hydrochloric acid (25ml.). The aqueous layer was basified with 10N sodium hydroxide solutionand extracted with ethyl acetate (50 ml.). The organic layer was dried(magnesium sulphate) and evaporated to dryness. The residual gum waspurified by preparative thin layer chromatography using ethylacetate/methanol/ammonia 6:1:1 v/v/v as developing solvent. Theappropriate zone of the chromatogram was isolated and extracted withmethanol/ammonia 10:1 v/v. The solvent was evaporated and the residuedissolved in ethyl acetate, filtered and added to a solution of maleicacid (0.05 g.) in ethyl acetate. The precipitate was filtered to give1-[2-(2-[(2,2,3,3-tetrafluoropropyl)guanidino]thiazol-4-ylmethylthio)ethylamino]-1-methylamino-2-nitroethylene(0.04 g.), m.p. 115°-118° (decomp.) containing 1.4 molar equivalents ofmaleic acid.

EXAMPLE 79

The process described in Example 78 was repeated using2-[2-(2,2,3,3,3-pentafluoropropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.15 g.) in place of2-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleand increasing the reaction time from 16 hours to 40 hours to give1-[2-(2-[(2,2,3,3,3-pentafluoropropyl)guanidino]thiazol-4-ylmethylthio)ethylamino]-1-methylamino-2-nitroethylene(0.04 g.), m.p. 114°-117° (decom.), containing 1.4 molar equivalents ofmaleic acid.

EXAMPLE 80

5-Methyl-N-nitroisothiourea (0.12 g.) and2-[2-(2-chloro-2,2-difluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.33 g.) were dissolved in ethanol (5 ml.) and allowed to stand at roomtemperature for 16 hours. The solvent was evaporated and the residualgum was purified by preparative thin layer chromatography using ethylacetate/methanol/ammonia 6:1:1 v/v/v as developing solvent. Theappropriate zone of the chromatogram was isolated and extracted withmethanol/ammonia 10:1 v/v. The solvent was evaporated and the residuewas dissolved in ethyl acetate, filtered and added to a solution ofmaleic acid (0.1 g.) in ethyl acetate. The precipitate was filtered togive2-[2-(2-chloro-2,2-difluoroethy)guanidino]-4-[2-(2-nitroguanidino)ethylthiomethyl]thiazole(0.28 g.), m.p. 112°-116°, containing 1.4 molar equivalents of maleicacid.

EXAMPLE 81

The process described in Example 80 was repeated using2-[2-(2,2,3,3,3-pentafluoropropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.14 g.) in place of2-[2-(2-chloro-2,2-difluoroethyl)guanidino]-4-[2-(aminoethyl)thiomethyl]thiazoleto give2-[2-(2,2,3,3,3-pentafluoropropyl)guanidino]-4-[2-(2-nitroguanidino)ethylthiomethyl)thiazolehydrogen maleate hemihydrate (0.1 g.), m.p. 140°-143°.

EXAMPLE 82

Dimethyl (propylsulphonylimido)dithiocarbonate (0.09 g.) and2-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.14 g.) were dissolved in ethanol (2 ml.) and allowed to stand at roomtemperature for 16 hours. The solvent was evaporated and the residualgum was dissolved in ethanolic methylamine (33% w/v, 5 ml.) and allowedto stand at room temperature for 16 hours. The solvent was evaporatedand the residual gum was purified by preparative thin layerchromatography using ethyl acetate/methanol/ammonia 6:1:1 v/v/v asdeveloping solvent. The appropriate zone of the chromatogram wasisolated and extracted with methanol/ammonia 10:1 v/v. The solvent wasevaporated and the residue was dissolved in ethyl acetate, filtered andadded to a solution of maleic acid (0.05 g.) in ethyl acetate. Theprecipitate was filtered to give2-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-4-[2-(2-propylsulphonyl-3-methylguanidino)ethylthiomethyl]thiazolehydrogen maleate (0.09 g.), m.p. 116°-118°.

EXAMPLE 83

The process described in Example 82 was repeated using2-[2-(2-chloro-2,2-difluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole(0.16 g.) in place of2-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleand there was thus obtained2-[2-(2-chloro-2,2-difluoroethyl)guanidino]-4-[2-(2-propylsulphonyl-3-methylguanidino)ethylthiomethyl]thiazolehydrogen maleate (0.12 g.), m.p. 107°-110°.

EXAMPLE 84

The process described in Example 73 was repeated using4-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-2-[3-aminopropylthio]pyrimidine(0.16 g.) in place of2-[2-(2,2-difluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleand there was thus obtained4-[2-(2,2,3,3-tetrafluoropropyl)guanidino-2-[3-(2-methylsulphonyl-3-methylguanidino)propylthio]pyrimidinehydrogen maleate (0.09 g.), m.p. 157°-159°.

The4-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-2-[3-aminopropylthio]pyrimidineused as starting material may be obtained as follows:

Thiophosgene (10 ml.) was dissolved in 1,2-dichlorobenzene (50 ml.) andcooled to 5°. Separate solutions of 2,2,3,3-tetrafluoropropylaminehydrochloride (16.7 g.) in water (50 ml.) and potassium carbonate (69g.) in water (150 ml.) were added simultaneously and dropwise with icecooling and vigorous stirring. After the addition the mixture wasstirred at room temperature for 2 hours then filtered and the organiclayer was separated and dried (magnesium sulphate). The solution wasdistilled at 200 mm.Hg and the fraction boiling from 25°-110° wascollected. This fraction was redistilled at 200 mm.Hg and the fractionboiling point 95°-105 ° collected to give a colourless oil (12.7 g.)containing 2,2,3,3-tetrafluoropropylisothiocyanate (83% w/w).

2,2,3,3-Tetrafluoropropylisothiocyanate (0.9 g.) and2-(3-phthalimidopropylthio)-4-aminopyrimidine (0.9 g.) were dissolved inacetonitrile (30 ml.) and heated under reflux for 64 hours. Theresulting suspension was cooled, filtered and the collected solid washedwith acetonitrile (10 ml.) to give a white solid (0.9 g.). This wasdissolved in a mixture of dimethylformamide (10 ml.) and saturatedethanolic ammonia solution (5 ml.) and treated with yellow mercuricoxide (0.8 g.). The mixture was stirred at room temperature for 3 hours.The solvent was evaporated and the black residue was triturated withethyl acetate and filtered. The solvent was evaporated and the residualgum was dissolved in ethanol (15 ml.) and added to a solution ofhydrazine (5 ml.) in ethanol (10 ml.). The mixture was stirred at roomtemperature for 2 hours then the solvent was evaporated. The residue wastriturated with 1N hydrochloric acid, filtered and the filtrate wasbasified with 10N sodium hydroxide solution. The product was extractedwith ethyl acetate, dried (magnesium sulphate) and the solvent wasevaporated to give4-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-2-[3-aminopropylthio]pyrimidine(0.5 g.) which was used without further purification.

EXAMPLE 85

The process described in Example 77 was repeated using4-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-2-[3-aminopropylthio]pyrimidine(0.12 g.) in place of2-[2-(2,2,-difluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazoleand there was thus obtained4-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-2-[3-[2-cyano-3-methylguanidino)propylthio]pyrimidinehydrogen maleate (0.06 g.), m.p. 164° (decomp.).

EXAMPLE 86

To a solution of2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(2-aminoethylthio)pyrazine (0.16g.) in ethanol (1 ml.) was added a solution of methylisothiocyanate(0.45 g.) in ethanol (1 ml.) and the mixture was stirred at roomtemperature for one hour. The mixture was evaporated, the residuebasified with 2N NaOH and extracted with ethyl acetate. The extractswere dried over magnesium sulphate, filtered, and the filtrateconcentrated to approximately 10 ml. A solution of maleic acid in ethylacetate was added in excess, the mixture diluted with ether and allowedto stand. The resulting solid was filtered and recrystallised fromethanol to yield 0.08 g. of2-[2-(2,2,2-trifluoroethyl)guanidino]-6-[2-(3-methylthioureido)ethylthio]pyrazinemaleate, m.p. 182°-183°.

The 2-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-aminoethylthio)pyrazineused as a starting material may be obtained as follows:

A solution of 2-amino-6-chloropyrazine (1 g.) in warm acetonitrile (15ml.) was cooled to room temperature. Trifluoroethylisothiocyanate (1.6g.) was added and the mixture stirred overnight. Furthertrifluoroethylisothiocyanate (1.6 g.) was added, and the mixture warmedgently on a steam bath for 2 hours, then heated under reflux for 2hours. The mixture was allowed to cool and evaporated to dryness toyield a brown solid. This was washed with water, 2N HCl solution, wateragain, and sucked dry. Recrystallisation from boiling toluene dilutedwith petroleum ether (b.p. 60°-80°) yielded colourless needles (0.77 g.)of 2-[3-(2,2,2-trifluoroethyl)thioureido]-6-chloropyrazine m.p.170°-172°.

To a solution of 2-[3-(2,2,2-trifluoroethyl)thioureido]-6-chloropyrazine(0.7 g.) in alcoholic ammonia (35 ml.) was added red mercuric oxide(0.65 g.) with stirring at room temperature. After stirring overnight,the black mixture was filtered and the black solid washed with alcohol.The resulting yellow filtrate was evaporated to give a yellow solid (0.7g.). Recrystallisation from hot toluene diluted with petroleum ether(b.p. 60°-80°) yielded colourless needles (0.5 g.) of2-[2-(2,2,2-trifluoroethyl)guanidino]-6-chloropyrazine m.p. 139°-140°.

Sodium hydride (50% w/w dispersion in oil; 0.114 g.) was addedportionwise to ethanol (2 ml.). To the resulting solution was added2-aminoethanethiol hydrochloride (0.134 g.) and the mixture stirred atroom temperature. 2-[2-(2,2,2-Trifluoroethyl)guanidino]-6-chloropyrazine(0.1 g.) was added and the mixture heated under reflux on a steam bathfor 22 hours. The mixture was cooled, evaporated, water added andextracted with ethyl acetate. The extracts were dried over magnesiumsulphate, filtered and the filtrate evaporated to yield2-[2-(2,2,2-trifluoroethyl)guanidino]-6-[(2-aminoethyl)thio]pyrazine asa gum (0.16 g.) which was used without further purification.

EXAMPLE 87

A solution of2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(3-aminopropylthio)pyrazine inwarm acetonitrile (15 ml.) was allowed to cool to room temperature. Asolution of methylisothiocyanate (0.15 g.) in acetonitrile (1 ml.) wasadded and the mixture stirred overnight. Evaporation to dryness gave ayellow solid which was recrystallised from a small volume of ethylacetate to yield2-[2-(2,2,2-trifluoroethyl)guanidino]-6-[3-(3-methylthioureido)propylthio]pyrazine(0.32 g.), m.p. 165°-167°.

The 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(3-aminopropyl)pyrazine usedas starting material may be prepared as follows:

Sodium hydride (50% w/w dispersion in oil; 0.57 g.) was added to ethanol(10 ml.) portionwise. To the resulting solution was added3-aminopropanethiol hydrochloride (0.75 g.) and the mixture stirred atroom temperature. 2-[2-(2,2,2-Trifluoroethyl)guanidino]6-chloropyrazine(0.5 g.) was added in one portion and the mixture heated under reflux onthe steam bath overnight. The mixture was cooled, evaporated, water (10ml.) added and the mixture extracted with ethyl acetate. The extractswere dried over magnesium sulphate, filtered and evaporated to yield anoil, which was chromatographed eluting with methanol/methylenechloride/ammonia 10:40:1 v/v/v to yield2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(3-aminopropylthio)pyrazine as apale yellow solid (0.39 g.) which was used without further purification.

EXAMPLE 88

A solution of3-[2-(2,2,2-trifluoroethyl)guanidino]-1-[2-(2-cyano-3-methylisothioureido)ethylthiomethyl]benzene(0.416 g.) in 33% w/v methylamine in ethanol (4 ml.) was kept at 20° for72 hours. Volatile material was evaporated in vacuo and the residue wasfractionated on a silica column (26 cm.×1 cm. diameter) eluted withethyl acetate/ethanol/triethylamine 9:2:1 v/v/v. The product,3-[2-(2,2,2-trifluoroethyl)guanidino]-1-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]benzene,had n.m.r. spectrum in d₆ dimethylsulphoxide and d₄ acetic acid usingtetramethyl silane as an internal standard (δ=0) containing thefollowing resonances (δ): 7.1 (4H, multiplet); 4.1 (2H, quartet); 3.7(2H, singlet); 3.2 (2H, triplet); 2.7 (3H, singlet); 2.5 (2H, triplet).

The3-[2-(2,2,2-trifluoroethyl)guanidino]-1-[2-(2-cyano-3-methylisothioureido)ethylthiomethyl]benzeneused as starting material may be prepared as follows:

m-Aminobenzyl alcohol (0.123 g.) and 2,2,2-trifluoroethylisothiocyanate(0.141 g.) were heated under reflux in acetone (5 ml.) for 2 hours.Volatile material was evaporated in vacuo and the crude residue wasfractionated on a silica gel column (20 cm.×1 cm. diameter) eluted withethyl acetate to give1-(3-hydroxymethylphenyl)-3-(2,2,2-trifluoroethyl)thiourea. The n.m.r.spectrum in CDCl₃ using tetramethylsilane as internal standard (δ=0) hadthe following resonances (δ): 7.2 (4H, multiplet); 4.6 (2H, singlet);4.3 (2H, multiplet).

The above thiourea (1.32 g.) was stirred in 1.6N alcoholic ammonia (50ml.) with mercuric oxide (3.4 g.) for 17 hours at 20°. The resultingmixture was clarified on the centrifuge and the supernatant wasevaporated in vacuo to a syrup which was further dried at 70°/0.1 m.m.to give 1-(3-hydroxymethylphenyl)-3-(2,2,2-trifluoroethyl)guanidine. Then.m.r. spectrum in d₆ dimethylsulphoxide using tetramethyl silane asinternal standard (δ=0) had the following resonances (δ): 6.9 (4H,multiplet); 4.4 (2H, singlet); 3.9 (2H, quartet).

The above guanidine (1.121 g.) was dissolved in dry tetrahydrofuran (40ml.) and thionyl chloride (0.7 ml.) was added. After 45 minutes at30°-40° volatile material was evaporated in vacuo to give1-(3-chloromethylphenyl)-3-(2,2,2-trifluoroethyl)guanidine as a syrup.

The above crude guanidine was dissolved in absolute alcohol (6 ml.) and2-aminoethanethiol hydrochloride (0.51 g.) added. The mixture wasstirred and cooled to 0°. 10.8N-sodium hydroxide (0.9 ml.) was addedover two minutes and the mixture was stirred at 0° for 2.75 hours. Theresulting mixture was clarified on the centrifuge and the supernatantwas evaporated in vacuo to a syrup which was shaken with water (15 ml.)and ethyl acetate (30 ml.). The ethyl acetate layer was separated andextracted with 2N hydrochloric acid (30 ml.) and the acid extract wasbasified with 2N sodium hydroxide and re-extracted with ethyl acetate(3×10 ml.). The extract was dried (MgSO₄) and evaporated in vacuo togive1-[3-(2-aminoethyl)thiomethylphenyl]3-(2,2,2-trifluoroethyl)guanidine asan oil.

The above amine (0.794 g.) was dissolved in alcohol (10 ml.) anddimethyl (cyanoimido)dithiocarbonate (0.379 g.) added. The mixture waskept at 20° while nitrogen was passed through for 20 hours. Volatilematerial was evaporated in vacuo and the residue was fractionated on acolumn of silica gel (40 cm.×2.5 cm. diameter) eluted with ethylacetate/ethanol/triethylamine 9:2:1 v/v/v to give3-[2-(2,2,2-trifluoroethyl)guanidino]-1-[2-(2-cyano-3-methylisothioureido)ethylthiomethyl]benzenewhich was used without further purification. The n.m.r. spectrum in d₆dimethylsulphoxide and d₄ acetic acid using tetramethylsilane asinternal standard (δ=0) had the following resonances (δ): 7.1 (4H,multiplet); 4.0 (2H, quartet); 3.6 (2H, singlet); 3.4 (2H, triplet); 2.5(2H, triplet); 2.4 (3H, singlet).

EXAMPLE 89

A solution of5-[2-(2,2,2-trifluoroethyl)guanidino]-3-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]-1,2,4-thiadiazolein 33% w/v methylamine in ethanol (4 ml.) was kept at 20° for 18 hours.Volatile material was evaporated in vacuo and the crude material wasfractionated on a silica column (26 cm.×1 cm. diameter) eluted with amethanol/ethyl acetate 1:50 v/v to give5-[2-(2,2,2-trifluoroethyl)guanidino]-3-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]-1,2,4-thiadiazole.The n.m.r. spectrum in d₆ dimethylsulphoxide using tetramethyl silane asan internal standard (δ=0) had the following resonances (δ): 4.2 (2H,quartet); 3.8 (2H, singlet); 3.3 (2H, multiplet); 2.7 (2H, triplet).

The5-[2-(2,2,2-trifluoroethyl)guanidino]-3-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]-1,2,4-thiadiazoleused as starting material may be prepared as follows:

To a suspension of [N-(2,2,2-trifluoroethyl)amidino]thiourea maleate(33.2 g.) in ethanol (160 ml.) was added bromine (5.27 ml.) over 10minutes. The mixture was stirred at 20° for 1 hour and evaporated invacuo to an oil which crystallised upon trituration with ether. Theproduct, 3-(2,2,2-trifluoroethyl)amino-5-amino-1,2,4-thiadiazolehydrobromide had m.p. 178°-180°. The free base, prepared by treating anaqueous solution of the hydrobromide with sodium bicarbonate, had m.p.145°-146°.

3-(2,2,2-Trifluoroethyl)amino-5-amino-1,2,4-thiadiazole (2.0 g.) andtetrahydropyranyloxyacetamidine hydrochloride (2.0 g.) was added to asolution of sodium ethoxide prepared from sodium (0.46 g.) and alcohol(50 ml.). The resulting mixture was stirred at 20° for 4 hours thenheated under reflux for 60 hours. Volatile material was evaporated invacuo and the residue was shaken with 2N hydrochloric acid (30 ml.) andethyl acetate (30 ml.). The aqueous layer was further extracted withethyl acetate (3×30 ml.) then the pH was adjusted to 10 with 2N sodiumhydroxide. The basified mixture was extracted with ethyl acetate (6×30ml.) and the combined extracts were dried (MgSO₄) and evaporated invacuo to give the crude product as an oil. It would be purified byfractionation on a silica gel column eluted with ethyl acetate to give5-[2-(2,2,2-trifluoroethyl)guanidino]-3-hydroxymethyl-1,2,4-thiadiazole,m.p. 123°-125°.

Part of the above crude material (1.28 g.) was dissolved in drytetrahydrofuran (40 ml.) and redistilled thionyl chloride (0.8 ml.) wasadded. After 1 hour at 25° volatile material was evaporated to give5-[2-(2,2,2-trifluoroethyl)guanidino]-3-chloromethyl-1,2,4-thiadiazole.This chloromethyl compound was dissolved in absolute alcohol (5 ml.) and2-aminoethanethiolhydrochloride (0.57 g.) was added followed by 10.8Nsodium hydroxide (1 ml.) with external ice cooling. The mixture wasstirred for 3 hours and the volatile material was then evaporated invacuo. The residue was shaken with 2N hydrochloric acid (10 ml.) andethyl acetate (10 ml.). The aqueous layer was basified with 2N sodiumhydroxide and extracted with ethyl acetate (3×20 ml.). The ethyl acetateextracts were dried (MgSO₄) and evaporated in vacuo to give5-[2-(2,2,2-trifluoroethyl)guanidino]-3-[(2-amino)ethylthiomethyl]-1,2,4-thiadiazoleas an oil (0.9 g.)

The above (2-amino)ethylthiomethyl derivative was dissolved in alcohol(10 ml.) and dimethyl (cyanoimido)dithiocarbonate (0.446 g.) was added.The mixture was kept at 20° for 17 hours and then evaporated in vacuo toa syrup which was fractionated on a silica gel column (25 cm.×2.5 cm.diameter) which was eluted by ethyl acetate. The product,5-[2-(2,2,2-trifluoroethyl)guanidino]-3-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]-1,2,4-thiadiazolewas used without further purification. The n.m.r. spectrum in d₆dimethylsulphoxide using tetramethylsilane as an internal standard (δ=0)had the following resonances (δ): 4.1 (2H, quartet); 3.7 (2H, singlet);3.5 (2H, quartet); 2.7 (2H, triplet); 2.5 (3H, singlet).

EXAMPLE 90

A mixture of2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-cyano-2-methylisothioureido)butyl]thiazole(0.23 g.) and N-methylhydrazine (0.6 g.) in dimethylformamide (15 ml.)was heated at 40°-45° for 40 hours. The solvent was removed and theresidue applied to 2 t.l.c. plates which were developed withchloroform/methanol/ammonia 9:1:0.1 v/v/v. The oil obtained wasconverted to a maleate in acetone to give3-amino-1-methyl-5-[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]-1H-1,2,4-triazoledimaleate (56.8 mg.), m.p. 181°-183°.

What is claimed is:
 1. A guanidine derivative of the formula: ##STR32##in which R¹ and R², which may be the same or different, are hydrogenatoms or branched or unbranched alkyl radicals of 1 to 10 carbon atoms,cycloalkyl radicals of 3 to 8 carbon atoms or cycloalkylalkyl radicalsin which the alkyl part is of 1 to 6 carbon atoms and the cycloalkylpart is of 3 to 8 carbon atoms, each of the alkyl, cycloalkyl andcycloalkylalkyl radicals being optionally substituted by up to 7 halogenatoms selected from fluorine, chlorine and bromine atoms, provided thatat least one of R¹ and R² is a halogen substituted alkyl, cycloalkyl orcycloalkylalkyl radical and provided that there is no halogensubstituent on the carbon atom of the alkyl, cycloalkyl orcycloalkylalkyl radical which is directly attached to the nitrogenatom;ring X is a thiazole or thiadiazole ring which may, where possible,carry a single optional substituent, the optional substituents on ring Xbeing selected from fluorine, chlorine, bromine and iodine atoms andalkyl, alkoxy and alkylthio radicals of 1 to 6 carbon atoms,trifluoromethyl, hydroxy and amino radicals; Z is a radical of theformula --Y--(CH₂)_(n) --NH₂, --Q--H or --Cl; Y is an oxygen or sulphuratom, a direct bond, a methylene, cis or trans vinylene or sulphinylradical or a radical of the formula NR⁴ in which R⁴ is a hydrogen atomor an alkyl radical of 1 to 6 carbon atoms; m is 0 to 4 and n is 1 to 5,provided that when Y is an oxygen atom, a sulphinyl radical or a radicalof the formula NR⁴, n is 2 to 5; and Q is an oxygen or sulfur atom or aradical of the formula NR⁴.
 2. The guanidine derivative of claim 1, inwhichR¹ and R² are selected from the group consisting of hydrogen atomsand 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,2-bromo-2,2-difluoroethyl, 2,2-dibromo-2-fluoroethyl, 2-fluoroethyl,2-chloroethyl, 2,2-difluoroethyl, 2,2-dichloroethyl,2-chloro-2-fluoroethyl, 2-bromo-2-fluoroethyl,2,2,3,3,3-pentafluoropropyl, 1,1,1,3,3,3-hexafluoroisopropyl,1,3-dichloro-1,1,3,3-tetrafluoroisopropyl,1-chloro-1,1,3,3,3-pentafluoroisopropyl, 1,3-difluoroisopropyl,2,2,3,3,4,4,4-heptafluorobutyl, 2,2,3,3-tetrafluorocyclopropyl,2-chloro-2-,3,3-trifluorocyclopropyl, 2,2-difluorocyclopropyl,2-chloro-3,3-difluorocyclopropyl, 2,2,3,3,4,4-hexafluorocyclobutyl,2-chloro-2,3,3,4,4-pentafluorocyclobutyl,(1,2,2,3,3-pentafluorocyclopropyl)methyl,(2-chloro-1,2,3,3-tetrafluorocyclopropyl)methyl,(1,2,2,3,3,4,4-heptafluorocyclobutyl)-methyl,(2-chloro-1,2,3,3,4,4-hexafluorocyclobutyl)methyl, methyl, ethyl,propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl andcyclopropylbutyl radicals provided that at least one R¹ and R² is ahalogen-substituted radical; ring X is a thiazole or thiadiazole ringeach optionally substituted, where possible by a fluorine, chlorine,bromine or iodine atom or by a methyl, methoxy, methylthio,trifluoromethyl, hydroxy or amino radical; and R⁴ is a hydrogen atom ora methyl radical.
 3. The guanidine derivative of claim 1, in which R¹carries at least one fluorine atom on the carbon atom which is onecarbon atom removed from the nitrogen atom to which the radical isattached and R² is a hydrogen atom.
 4. The guanidine derivative of claim1, in which ring X is a thiazole ring in which the guanidine radical issubstituted at the 2-position.
 5. The guanidine derivative of claim 1,in which m is 0.